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Delivery of cancer therapies by synthetic and bio-inspired nanovectors



As a complement to the clinical development of new anticancer molecules, innovations in therapeutic vectorization aim at solving issues related to tumor specificity and associated toxicities. Nanomedicine is a rapidly evolving field that offers various solutions to increase clinical efficacy and safety.


Here are presented the recent advances for different types of nanovectors of chemical and biological nature, to identify the best suited for translational research projects. These nanovectors include different types of chemically engineered nanoparticles that now come in many different flavors of ‘smart’ drug delivery systems. Alternatives with enhanced biocompatibility and a better adaptability to new types of therapeutic molecules are the cell-derived extracellular vesicles and micro-organism-derived oncolytic viruses, virus-like particles and bacterial minicells. In the first part of the review, we describe their main physical, chemical and biological properties and their potential for personalized modifications. The second part focuses on presenting the recent literature on the use of the different families of nanovectors to deliver anticancer molecules for chemotherapy, radiotherapy, nucleic acid-based therapy, modulation of the tumor microenvironment and immunotherapy.


This review will help the readers to better appreciate the complexity of available nanovectors and to identify the most fitting “type” for efficient and specific delivery of diverse anticancer therapies.


Cancer causes approximately 10 million deaths per year worldwide for around 18 million new cases [1]. Advanced understanding of cancer biology and continuous improvement of treatments such as radiotherapy, chemotherapy and more recently immunotherapy have steadily ameliorated patient survival over the years. In many cases, these treatments remain associated with adverse effects and limited efficacy due to a lack of tumor specificity. Resistances to single treatments are commonly addressed by combination therapies that can further increase the risks of life-threatening toxicities. Moreover, some categories of molecules such as hydrophobic drugs, radioisotopes, toxins or nucleic acids cannot be injected systemically to patients because of their instability or of extensive off-target effects. These limitations can be overcome through vectorization using nanocarriers that will increase drug solubility and bioavailability, improve the targeting of the cancer microenvironment, augment local drug concentration in tumors and potentiate the efficacy of therapeutic combinations [2, 3] (Fig. 1).

Fig. 1

Advantages of vectorization for delivering cancer therapies. The clinical efficacy of therapeutic molecules (e.g. chemotherapeutic drugs, radionuclides, nucleic acids, antibodies) relies on efficient tumor delivery and limited off-targeting. Nanovectors of different natures (e.g. nanoparticles, extracellular vesicles, viruses) can improve the transport of these molecules in the bloodstream by increasing their solubility, half-life and bioavailability, and by helping the crossing of biological barriers. Tumor delivery is also enhanced by improved targeting of the tumor microenvironment, leading to the accumulation of the therapeutic molecules in the tumors and thus potentiating the use of combination therapies

Specific targeting, which is key to increase treatment efficacy while reducing detrimental off-target effects, remains a major scientific challenge in multiple areas of therapeutic research. In cancer therapy, vectorization approaches have recently diversified with the development of new families of nanovectors (1 to 1,000 nm) created by chemical engineering (e.g. nanoparticles) [3] or derived from the biological world (e.g. bacteria, viruses, extracellular vesicles) [4]. Although this adds to the complexity of drug development, efficient vectorization appears as essential to further improve the safety and efficacy of both current and future cancer therapies. In this review, we chose to focus on nanovectors that are able to protect and to carry therapeutic payloads to tumors following a systemic injection. This does not include antibody-mediated vectorization [5], cancer vaccination strategies [6] or vectorization for imaging [7] – for instance for guided surgery – which have been reviewed elsewhere. We first introduce the various families of nanovectors available today, including the different subtypes of organic and inorganic nanoparticles (Fig. 2), cell-derived extracellular vesicles (EVs), virus-like particles (VLPs) (e.g. plant and animal viruses, bacteriophages), oncolytic viruses (OVs) and bacterial minicells (Figs. 3 and 4). These vectors display different physical and structural properties that dictate their abilities to be coupled to different types of therapeutic molecules (e.g. chemotherapeutic drugs, radioisotopes, proteins, nucleic acids) and make them adapted to different biological and clinical situations. A clear understanding of the advantages and limitations of each of these nanovectors (Table 1) to transport different therapeutic agents (Table 2) and of their evolving potential will help developing better vectorization approaches in the future.

Fig. 2

Chemically engineered nanoparticles for cancer therapy. This class of nanovectors is commonly divided between inorganic and organic nanoparticles. Inorganic nanoparticles (e.g. metallic, silica, carbon, quantum dots) are characterized by a high stability, a low biodegradability and intrinsic electronical and optical properties suitable for cancer imaging and theranostics. Because of their solid core, therapeutic molecules are generally conjugated on their surface and may be exposed to rapid degradation in vivo. Organic nanoparticles (e.g. lipid-based, macromolecular assemblies) exhibit a lower stability but a good biocompatibility and multiple possibilities of drug functionalization on their surface or their inner space. Hybrid nanoparticles combine the advantages of both inorganic and organic families to improve the biocompatibility and the stability of the nanovector

Fig. 3

Biological and bio-inspired nanovectors for cancer therapy. These nanovectors have been derived from different types of organisms and exhibit high biocompatibility and extensive engineering possibilities. Extracellular vesicles derive from eukaryotic cell membranes and naturally transport different types of biomolecules (e.g. proteins, RNA). Bacterial minicells are achromosomal 400-nanometer vesicles that can be generated by genetic engineering of bacteria and have been recently used to vectorize various types of therapeutic molecules. Virus-like particles are basically viruses (e.g. bacteriophages, plant viruses, eukaryotic viruses) stripped of their replicative capacity; they exist as naked or enveloped capsids and sometimes require a non-replicative template genome for their assembly. On the contrary, oncolytic viruses are tumor-specific, live-replicating viruses with intrinsic cytotoxic and immunoactivating properties; they can equally be naked or enveloped and may be modified by genetic engineering to transport therapeutic transgenes that will be expressed exclusively by infected malignant cells

Fig. 4

Biogenesis of biological nanovectors. Biological nanovectors are either derived from prokaryotic (bacterial minicells) or eukaryotic (extracellular vesicles) cells, or from viruses (oncolytic viruses and virus-like particles). Bacterial minicells are achromosomal vesicles obtained upon genetic engineering (deletion of the Min operon) from ectopic septation of Gram-positive or Gram-negative bacteria. Extracellular vesicles are produced by all eukaryotic cells by outward budding of the plasma membrane (microvesicles) or through inward budding and exocytosis (exosomes). Regarding viruses, whereas live-attenuated oncolytic viruses carry a complete genome and thus retain a replicative capacity specific for transformed cells, virus-like-particles are only constituted of structural proteins and are consequently not competent for replication

Table 1 Main properties of the different families of nanovectors
Table 2 Suitability of the different families of nanovectors for the vectorization of anti-cancer therapeutics

Types of nanovectors


Chemically engineered nanoparticles form a vast class of nanovectors with a wide variety of structures, sizes and compositions [8, 9] (Fig. 2). Among the inorganic family, the most studied are metallic (e.g. gold, iron oxide) nanoparticles that display unique optical and electronic properties particularly favorable for biomedical imaging [10]. Because of their solid core, drug functionalization consists in surface bonding and exposes conjugated drugs to both degradation and exchange dynamics in the bloodstream. Their use in therapy is also limited by a low biodegradability. Mesoporous inorganic nanoparticles – mostly biodegradable, silica-based – constitute an alternative to protect drugs within a porous structure but their safety profile still needs characterization [11, 12]. On the other hand, the organic nanoparticle family exhibits better biocompatibility and biodegradability, making those more suitable for therapeutic applications. The first organic subfamily encompasses natural (e.g. protein- and polysaccharide-based) and synthetic (e.g. polylactic acid derivatives, dendrimers, fluorescent organic nanoparticles) macromolecular nanoassemblies (also improperly called polymeric nanoparticles) that possess a good stability and display numerous free functional groups endowing them with a high loading capacity [8, 13]. These properties explain the growing interest for such nanoassemblies in cancer therapy even if the in vivo characterization of each of their subunits remains challenging. The second organic subfamily contains lipid-based nanoparticles that are the most represented in preclinical and clinical studies due to their unmatched biocompatibility [8, 14, 15]. They basically consist in lipid monolayered (i.e. micelles) or bilayered (i.e. liposomes) nanovesicles and can vectorize a broad range of molecules with distinct physicochemical properties; hydrophobic drugs can be embedded within the lipid bilayer of liposomes or loaded in the core of micelles while hydrophilic drugs are either entrapped in the aqueous core of liposomes or displayed on their surface [16, 17]. However, lipid-based nanoparticles still face several limitations among which a low loading capacity and a relative lack of stability leading to drug leakage. New hybrid nanoparticles have recently been developed to combine the respective advantages of the different subfamilies, namely solid-lipid, hybrid polymer-lipid [18] and hybrid organic-inorganic nanoparticles [19].

Nanoparticular vectorization is traditionally believed to take advantage of the enhanced permeability and retention (EPR) effect that results from the abnormal tumor vasculature causing preferential extravasation and increased concentration of nanoparticles in tumors [9, 20, 21]. Recent evidence also supports the existence of an additional active uptake process through endothelial cells [22]. However, even though the global biodistribution of nanoparticles seems to rely mostly on these mechanisms, only actively targeted nanoparticles efficiently infiltrate tumors and enter malignant cells [2, 23]. This requires coupling nanoparticles to targeting molecules – directed against surface antigens overexpressed on tumor cells – including but not limited to proteins (e.g. antibodies [24, 25]), aptamers [26], peptides [27] or polysaccharides [28]. An emerging alternative modality of active tumor targeting is the external magnetic guidance of metallic nanoparticles to promote preferential tumor extravasation [29]. Their coupling to iRGD peptides – recognized by the αvβ3 integrin overexpressed on both the tumor neovasculature and some malignant cells – was also reported to improve the specific extravasation of nanoparticles in tumors [23, 27].

Overall, nanoparticles act as multimodal platforms that can be extensively engineered to improve both tumor targeting and the delivery of combined treatments to malignant cells; they are perfectly suited to increase both the half-life of therapeutic molecules in the bloodstream and their concentration in tumors while lowering their systemic toxicity [3]. Nevertheless, they face several biological barriers that have limited their clinical use so far (Fig. 5). These hurdles can however be overcome by rational engineering [3, 9]. As such, clearance by the mononuclear phagocytic system is usually diminished by functionalizing nanoparticles with non-immunogenic hydrophilic polymers such as polyethylene glycol (PEG) or zwitterionic ligands [30]; this prevents interactions with immune cells – thereby enhancing their half-life in blood – but can also decrease internalization by tumor cells. Of note, PEG can also be recognized by-anti-PEG antibodies that will impair vectorization efficacy and may generate immune-related adverse effects [31]. To improve the cellular intake of PEGylated nanoparticles within tumors, stealth polymer coatings that specifically dissolve in the tumor microenvironment (TME) have been developed [32]. Stealthiness can also be improved by entrapping nanoparticles into cellular membranes to mimic biological vesicles [19]. A lot of work has been performed lately to study the effect of the protein corona formation around nanoparticles, as it can drastically impact their stealthiness and tumor uptake [33,34,35]. Tunable drug release solutions have also been created to promote a specific delivery of packaged drugs exclusively in tumors. Hence, so-called ‘smart’ drug delivery systems enclose pH-, enzyme-, heat- or photo-sensitive molecules which conformations change in tumors to specifically destabilize the nanoparticle structure and release the therapeutic cargo [9, 36]. To improve nanoparticle tissue penetration and diffusion through the dense extracellular matrix (ECM) in tumors, several combinations of ECM-modifying molecules and nanoparticles are also currently under investigation [37]. Finally, a major pitfall for vectorization with nanoparticles is their trapping in endo-lysosomes after endocytosis, which exposes the therapeutic cargo to degradation. Available solutions include coupling nanoparticles to endosomal escape domains or proton sponges to destabilize endosomes and promote drug release toward the cytoplasm [38].

Fig. 5

From the blood to the tumor cell: the difficult journey of nanovectors. Systemically injected nanovectors face several biological barriers to reach the tumor microenvironment and exert their therapeutic effect in malignant cells. First, filtering organs such as the liver (for nanovectors > 5 nm) or the kidneys (for nanovectors < 5 nm) eliminate an important fraction of the injected nanovectors. Nanovectors then extravasate from the bloodstream to the tumor either because of an increased vascular permeability (Enhanced Permeability and Retention effect) or by active transcytosis through endothelial cells. The nanovectors have to overcome the interstitial pressure and to diffuse in the extracellular matrix to reach tumor cells. This can be partially improved by active targeting strategies through nanovector engineering. Once reaching the cancer cells, nanovectors can be internalized by several mechanisms (e.g. passive or virus-mediated fusion, endocytosis, macropinocytosis) depending on their origin, size, composition and functionalization. The final difficulty consists in delivering the therapeutic cargo in the appropriate cellular compartment – generally the cytoplasm – to achieve optimal therapeutic efficacy. This usually requires further vector engineering (e.g. endosomal escape domains, pH-sensitive moieties), in particular for non-biological nanoparticles.EVs: Extracellular Vesicles; VLPs: Virus-Like Particles; OVs: Oncolytic Viruses

Biological and bio-inspired nanovesicles

The biological world provides attractive alternatives to artificial lipid-based nanoparticles. Extracellular vesicles (EVs) are naturally occurring vesicles produced by eukaryotic cells and play important roles in intercellular communications [39]. They naturally package a broad range of cargos, from nucleic acids to proteins or lipids. There are two main types of EVs at the nanometer scale, namely microvesicles (50 nm to 1 μm) and exosomes (50 to 150 nm) that differ by their biogenesis and composition. Microvesicles directly bud outward of the plasma membrane while exosomes are generated from the inward budding of endosomal membranes and are released in the extracellular environment by exocytosis (Fig. 4). Because of their low immunogenicity and their efficient intake by cells [40], EVs have been investigated as drug nanocarriers for cancer therapy [41]. Therapeutic drugs can be loaded either directly into pre-formed vesicles or through modification of the EV-producing cells (e.g. drug exposure, transfection) to entrap the cargo into EVs during their formation [42, 43]. Although still controversial [44], EVs are suspected to possess inherent targeting capacities depending on their progenitor cell type [45]; tumor cell-derived exosomes thus appear to preferentially home to their cell types of origin in vitro compared with untargeted liposomes [46]. As for liposomes, the surface of EVs can be modified with targeting molecules or PEG [47]. Nevertheless, the lack of content standardization and of large-scale production methods still hinders their clinical use; the development of EV-like nanovesicles, which are basically liposomes enriched with membrane proteins to enhance cellular intake, is expected to help overcoming some of these limitations [48]. A derivative from this idea are “virosomes” (150 to 500 nm) that are composed of a synthetic lipid bilayer containing viral or parasitic fusogenic glycoproteins [49, 50]. Those take advantage of the ability of viral envelopes to recognize the targeted cells and to promote direct fusion with the plasma membrane, hence skipping the potential degradation of the encapsulated cargo into late endosomes after endocytosis (Fig. 5). Other strategies use cell-derived nanovesicles to camouflage other types of vectors (e.g. nanoparticles, viruses) to take advantage of their intrinsic properties and to escape neutralizing antibodies [51,52,53,54].

The trend to exploit bio-derived nanostructures for cancer therapy extends to different families of pathogens. Bacterial minicells (200 to 400 nm) are achromosomal vesicles produced by bacteria upon ectopic septation [55] (Fig. 4), an asymmetric division obtained by deleting the Min operon [56]. Minicells can be produced from Gram-positive and Gram-negative bacteria and contain all the molecular components of the parent cell except for the chromosome. Because of their vesicular structure, they are an alternative to lipid-based nanoparticles for cancer therapy (Fig. 3). Although Gram-positive minicells are negative for lipopolysaccharides (LPS) and may be ultimately more adapted for clinical use, most studies have used Gram-negative minicells that can be easily redirected to cancer-specific receptors (e.g. HER2/neu) with bispecific antibodies targeting both the LPS O-antigen on minicells and a tumor marker [57, 58]. Bacterial minicells can package a wide variety of molecules with different structures, charges and solubilities in an easier way than with lipid-based nanoparticles [55, 59]. They display a high loading capacity – up to 1,000 times higher than liposomes – following simple drug importation through the outer membrane via the non-specific FadL or OmpW channels. To confirm their interest in cancer therapy [60, 61], comprehensive studies are still needed to better characterize their properties, among which their immunogenic profile. Their safety however pleads for further developments, as was demonstrated in three recent phase I clinical trials that tested Epidermal Growth Factor Receptor (EGFR)-targeted minicells loaded with either paclitaxel [62], doxorubicin [63] or miRNA mimics [64] in patients with end-stage solid cancers, glioblastoma or mesothelioma, respectively.

Virus-like particles

Viruses are extensively studied in therapeutic vectorization due to their active cell entry mechanisms, biocompatibility and well-characterized structures. Virus-like particles (VLPs) were developed to mimic animal, plant or bacteria viruses without retaining the ability to replicate in human cells [65] (Figs. 3 and 4). They are viral capsids with an icosahedral or filamentous structure composed of self-assembled proteins. Their diameters range from 25 (e.g. parvoviridae) to several hundred (e.g. herpesviridae) nanometers and they can contain a non-infectious genome composed of single- or double-stranded RNA or DNA [66]. Icosahedral VLPs can be used as genome-free particles such as the ones derived from the MS2 bacteriophage [67], which spontaneously assemble during protein production in bacteria, or from the cowpea mosaic virus (CPMV) [68]. On the contrary, filamentous VLPs derived from plant viruses and bacteriophages generally require a template genome for capsid proteins to assemble around it and form a rigid or flexible tube which length and width are determined by the capsid protein and the genome size. In addition, some viruses (e.g. retroviridae) present an envelope composed of an external lipidic membrane acquired while budding from the host cell surface [69]. As VLPs contain non-self proteins and potential pathogen-associated molecular patterns, they can be immunogenic and were mostly assessed as anti-cancer immuno-stimulatory treatments [70]. Their use as vaccines showed a good safety profile that makes them suitable for future use as nanovectors. Nevertheless, repeated treatments could promote the generation of antibodies and clearance by immune cells resulting in decreased tumor delivery. Capsid PEGylation or elimination of immuno-dominant epitopes can however limit these issues [71].

Because of their viral nature, VLPs are perfectly adapted to the delivery of therapeutic nucleic acids [72] but empty capsids can also be modified to transport other types of molecules. As such, the fixed structures of VLPs allow for extensive genetic and chemical engineering. Examples include tobacco mosaic virus VLPs that can be loaded by simple infusion and ionic interactions with their inner surface [73], the hepatitis B virus capsid that can be disassembled and re-assembled to capture a compound [74], or the functionalization of MS2 VLPs by inserting genetically a cystein residue in the capsid [75]. Interestingly, filamentous VLPs show a natural biodistribution to tumors after systemic injection, which could be mediated by their physical behavior in the tumor microvasculature [76, 77]. Non-human virus-based VLPs did not evolve to recognize human cell receptors; they produce less off-target effects but require genetic or chemical retargeting to malignant cells. Common modifications involve the retargeting of VLPs with cancer-specific peptides [78], aptamers [75] or other molecules [72, 79], or the pseudotyping of enveloped VLPs with exogenous proteins. Similarly, twelve serotypes of adeno-associated viruses (AAVs) have been identified so far [80] and could be used to target different types of cancers. In addition, VLPs from plant or bacteria viruses cannot easily escape human endo-lysosomes and display lower transfer efficacy, even after retargeting [81,82,83,84]. Strategies similar to the ones used with nanoparticles for endosomal escape and cargo delivery are being tested to overcome these limitations [78]. On the opposite, VLPs derived from human pathogens benefit from coevolution to achieve efficient gene transfer inside human cancer cells (Fig. 5).

Oncolytic viruses

Contrary to VLPs for which the non-replicative nature is a major determinant of their clinical safety and intermediate immunogenicity, oncolytic viruses (OVs) display all the properties of natural viruses except that their replication is restricted to malignant cells [85] (Fig. 4). The diversity of OVs has been reviewed extensively elsewhere [86] and is summarized in Fig. 3. OVs are either naturally attenuated viral strains or genetically engineered viruses that harness cancer hallmarks such as altered metabolism, immunosuppression or resistance to cell death that make tumors more sensitive than healthy tissues to viral infections. Tumor cells also commonly overexpress surface proteins that are used by some viruses for cell entry [87, 88]. For many oncolytic RNA viruses, tumor specificity mainly depends on defects in the innate antiviral pathways commonly acquired by malignant cells during tumor evolution [89, 90], while DNA viruses can be modified with tumor-specific promoters [91]. Contrary to other nanovectors, the tumor specificity of OVs thus mostly relies on post-entry restriction rather than selective entry through specific surface markers. They also exhibit therapeutic properties on their own as they can both directly kill tumor cells and activate a diversity of immune cell types involved in the anti-tumor responses [86, 92]. After two decades, more than a hundred trials and few regulatory approvals for clinical use [93,94,95], they have demonstrated a very good safety profile but a somewhat modest therapeutic efficacy in humans.

To improve their intrinsic anti-cancer properties, OVs are commonly armed to vectorize therapeutic transgenes that will be expressed by infected malignant cells in the TME, thereby making them bona fide nanovectors [96]. Viruses have evolved to deliver efficiently their genome in host cells and are thus perfectly designed to vectorize nucleic acids (Fig. 5). The first OV to be approved by the US and EU regulatory agencies in 2015 was the recombinant herpesvirus Talimogene laherparepvec (T-VEC) that encodes the Granulocyte-Macrophage Colony-Stimulating Factor to enhance its immunostimulatory properties [94, 97]. The transgene capacity of viruses is however limited by the fitness cost – the longer the genome, the longer it takes to replicate – and the size limit of the viral particle; DNA viruses generally exhibit a higher transgene capacity than RNA viruses. OV replication capacity allows both spreading of the transgene in the tumor and its sustained expression over time [98]. As with VLPs, surface molecular coupling is theoretically possible – especially for non-enveloped viruses – to enable intracellular delivery of drugs in specific cells.

The current standard for OV treatment is intratumoral injection with the limit that only reachable tumors can be treated, but recent evidence of viral replication in tumors following intravenous administration in patients have been reported [99,100,101,102,103]. Despite pre-existing immunity having no measurable effect on the therapeutic outcome after intratumoral injection, innate and adaptive immune responses against circulating viruses may restrict their efficacy after intravenous administration [104, 105]. PEGylation of OVs [106, 107] or switching OV species during the course of treatment [108, 109] can improve stealthiness and enhance treatment efficacy. Enveloped viruses can also be pseudotyped with different viral envelops [110,111,112], while changing the serotype of non-enveloped viruses could evade the immune response [113,114,115]. Finally, the titration of OVs by healthy cells after non-specific entry – distinct from their tumor-specific replication and killing – can be answered by retargeting OVs to tumor-specific surface antigens through genetic engineering. Advances made in the field of nanoparticles for chemical modifications are also expected to lead to alternative solutions [107].

Applications in cancer therapy


Cancer chemotherapeutics are a large family of chemical drugs [116] that affect highly proliferating malignant cells and exhibit diverse modes of action from cell cycle arrest to cell death induction and epigenetic modulation. These molecules often lack tumor specificity and healthy proliferative cells are frequently impacted, thereby causing different debilitating symptoms. Consequently, vectorization of chemotherapeutics is critical to improve their tumor specificity and diminish side toxicities. Here, we present an overview of how the different families of nanovectors can help bypassing the major limitations of chemotherapies, including their poor aqueous solubility, their lack of tumor specificity and the acquisition of resistances. The advantageous physical properties of some nanovectors that can be exploited in combinatorial strategies with chemotherapies are also discussed.

Solving drug insolubility

Chemical drugs for cancer treatment vary widely by their structures, charges and solubilities that can limit their clinical use, an illustrative example being the high hydrophobicity of taxanes [117]. The nanomedicine field however provides numerous solutions for drug vectorization whether they are hydrophobic (e.g. paclitaxel, cisplatin) or amphipathic (e.g. doxorubicin, 5-fluorouracil). As explained above, the diversity of chemically engineered nanoparticles with variable loading and functionalization possibilities makes them the most suitable for vectorizing chemotherapeutic drugs [9, 118] (Table 2). Hydrophilic drugs can be easily encapsulated inside liposomes, adsorbed in pores of silica nanoparticles or conjugated on metallic or polymeric nanoparticles using reactive hydroxyl, carboxyl, amino or thiol groups. Hydrophobic molecules are commonly loaded in micelles or solid-lipid nanoparticles or inserted in the lipid bilayer of liposomes. Nanoparticles are also used to vectorize hydrophobic epigenetic modulators (e.g. inhibitors of histone deacetylases or DNA methyltransferases) to improve their pharmacokinetics and therapeutic efficacy [119,120,121,122]. Macromolecular nanoassemblies and lipid-based nanoparticles have been used to vectorize almost all types of chemotherapeutics and several nanomedications have either already been approved by the FDA for cancer treatment or are currently evaluated in clinical trials [8, 123] (Table 3). It is interesting to note that cancers with very different profiles, from end-stage solid tumors to hematological malignancies, can be eligible to nanovectorization of chemotherapeutics. As an example, the nab-paclitaxel formulation (Abraxane®) – composed of paclitaxel fused to human albumin nanoparticles – has demonstrated improved safety and efficacy compared to free paclitaxel [136] and is approved against non-small cell lung cancer, metastatic pancreatic cancer and as a second-line treatment for metastatic breast cancers [137].

Table 3 Representative examples of the advancement of nanovectors in cancer therapy

Other types of nanovectors are currently studied to transport and deliver chemical drugs to tumors (Table 2). The characterization of VLPs at the atomic level allows for precise chemical coupling strategies similar to the ones used for nanoparticles. For example, doxorubicin coupling to Physalis Mottle virus icosahedral VLPs [81] or to truncated hepatitis B virus core antigen (tHBcAg) VLPs [138] improved both its cellular uptake and cytotoxicity against malignant cells. Doxorubicin and mitoxantrone were also passively loaded into CPMV [139] and filamentous plant viruses VLPs [140,141,142] by exploiting for the latter the negative charges of the inner side of the particles. Simple dissociation/association of tHBcAg allows for passive dual loading of polyacrylic acid (PAA) along with doxorubicin that will be released at low pH when no longer retained by protonated PAA [79]. EVs on their part display similar vectorization abilities as liposomes. They were shown for instance to deliver doxorubicin [143] or paclitaxel [144] in vitro to breast or prostate cancer cells, respectively, or paclitaxel to lung cancer cells after systemic administration in mice [145]. Packaging of decitabine in erythro-magneto-hemagglutinin nanovesicles showed a specific delivery to prostate cancer xenografts under in vivo magnetic guidance and a significant tumor mass reduction at a lower dose than with free decitabine [146]. Among the bio-inspired nanovectors, bacterial minicells may be the more promising as they can incorporate a wide variety of chemotherapeutic agents without drug efflux up to several days [55]. Their encouraging early clinical results in two phase I clinical trials that used EGFR-targeted bacterial minicells containing either doxorubicin or paclitaxel to treat patients with advanced solid tumors [62, 63] however need to be confirmed.

Improving tumor specificity

The lack of tumor specificity for chemotherapies causes off-target effects and limits clinical efficacy by decreasing drug concentration in tumors. For instance, doxorubicin displays elevated hematological and cardiac toxicities as a free molecule [147]. It has been vectorized as early as the 1990s in the first FDA-approved nanodrug Doxil®, which is currently approved for the treatment of ovarian cancer, multiple myeloma, metastatic breast cancer and Kaposi’s sarcoma. Doxil® is composed of doxorubicin encapsulated in untargeted, PEGylated liposomes that enable a high concentration of doxorubicin in tumors correlated with a higher tolerability compared to free doxorubicin [148]. This formulation was followed by many other combinations of chemotherapeutic drugs with numerous types of nanoparticles [124]. As with the Doxil® liposomal formulation, their tumor specificity mostly relied on passive targeting due to destabilized tumor vasculature and the resultant EPR effect. Based on a similar idea, the natural tumor distribution of filamentous VLPs [77, 149] can also be exploited for this purpose; PEGylated Potato Virus X (PVX) VLPs passively loaded with doxorubicin were indeed shown to elicit a better control of breast cancer xenografts in immunodeficient mice than doxorubicin alone [140]. However, a combination of PVX and doxorubicin was more effective than doxorubicin-loaded PVX in an immunocompetent melanoma model [141], suggesting that VLPs elicit an adjuvant anti-tumor immune response that participates in the therapeutic effect and pleading for the use of immunocompetent animal models for future evaluations.

Current studies mostly focus on actively targeted nanodrug formulations to enhance interactions of the nanoparticles with malignant cells after having reached the TME [23, 24, 27]. Several strategies have demonstrated increased drug concentration in tumors and enhanced therapeutic efficacy compared with the corresponding free molecules or untargeted nanovectors [23, 150]. In a preclinical study, paclitaxel-loaded nanocapsules constituted of a lipid core surrounded by a surfactant were targeted to the altered tumor vascular endothelium with an iRGD peptide [151]. The authors demonstrated that the targeted nanoparticles concentrated in hepatic tumors, induced specific cytotoxicity and were better tolerated than non-targeted nanoparticles. Another recent study showed that hybrid solid-lipid nanoparticles decorated with folic acid can significantly increase the concentration of carboplatin and paclitaxel in tumors cells in a murine cervical cancer model [152]. EGFR-targeted, doxorubicin-containing bacterial minicells were demonstrated to rapidly locate in spontaneous gliomas in dogs, a tumor usually difficult to reach because of the blood-brain barrier [60]. Another approach for active tumor delivery is to target the hypoxic center and acidic microenvironment of tumors, in particular using the pH (low) insertion peptide (pHLIP) [153]. An example for this strategy is the use of doxorubicin-loaded bacterial minicells with a pHLIP added to their membrane, which successfully invaded the necrotic and hypoxic regions of orthotopic murine breast cancers and achieved a significant tumor reduction compared to both free drug and untargeted minicells [154].

Fighting resistance

Cancer cells commonly develop resistance against chemotherapies, for instance by acquiring a multidrug resistance (MDR) phenotype. This can result from the expression of ATP-dependent transporters that promote the efflux of drugs outside the cell to escape death induction [155, 156]. Nanovectors enable drug immobilization and limit efflux, thereby enhancing drug concentration in tumor cells. They can also carry several drugs at the same time to strike cancer cells on different fronts simultaneously and prevent therapeutic escape [157]. Such strategies can combine several chemotherapies [152] or different types of treatments such as a combination of a chemotherapeutic drug with a siRNA [158]. Doxorubicin-coated, multifunctional mesoporous silica nanoparticles containing a siRNA against the P-glycoprotein (Pgp) drug exporter showed targeted Pgp knockdown and a synergistic inhibition of resistant breast tumor growth in preclinical models [159]. A similar approach used sequentially (i) CD33- or EGFR-targeted bacterial minicells containing a plasmid coding for shRNAs against MDR pumps and (ii) chemotherapies [160]; mice bearing drug-resistant colorectal, breast or uterine tumors were efficiently treated without toxicity as a thousand-fold less drug and shRNA were used compared to conventional systemic treatment. Another way to circumvent tumor resistance is to use highly cytotoxic compounds – such as the PNU-159682 metabolite [161] – that cannot be injected systemically because of their high toxicity. Systemic vectorization of this drug in EGFR-targeted bacterial minicells showed significant tumor reduction and immune activation with no side effects in immunocompetent breast and colorectal murine models but also lung and colorectal human cancer xenografts [162].

Exploiting intrinsic physical properties

Some chemically engineered nanoparticle families have intrinsic physical properties that make them suitable for combined therapies. As such, gold nanoparticles can be used for photothermal therapy, which consists in a local vibrational heat generation through the absorption of specific wavelengths of light [163]. Super Paramagnetic Iron Nanoparticles (SPIONs) on the other hand can be used for hyperthermia, a local heat generation under a magnetic field [164]. Those two phenomena have demonstrated a moderate therapeutic efficacy on their own but can sensitize cancer cells to chemotherapies loaded in the same nanoparticles [165]. Indeed, hyperthermia and photothermia inhibit the repair of DNA lesions (e.g. double-strand breaks) generated by chemotherapy or radiotherapy [166]. Several clinical trials involving the use of hyperthermia as adjuvant for chemotherapy are ongoing [167]. An example is the use of a near-infrared-responsive polypeptide nanocomposites charged with doxorubicin and capable of heat generation and heat-sensitive nitric oxide (NO) gas delivery [168]. This combination of photothermia, NO gas therapy and chemotherapy achieved complete breast tumor regression in mice after a single near-infrared irradiation. Hyperthermia can also be used to release chemotherapeutics enclosed in hybrid delivery systems constituted of nanoparticles associated with thermosensitive molecules [169]. Regarding epigenetic modulation, some studies suggest that metallic and silica nanoparticles could directly induce modifications of DNA methylation or of histone acetylation and disrupt miRNA expression [170, 171], but the significance of these modifications in the context of cancer treatment is still to be investigated.

The nanovectorization of chemotherapeutic drugs has been historically dominated by the use of organic nanoparticles (Table 2), supported by their unmatched diversity of structures and compositions (Fig. 2). This led to different clinical successes resulting in several drug approvals (Table 3). However, the more recent advances in vesicular nanovectors (e.g. bacterial minicells, EVs), provide new solutions with enhanced biocompatibility (Table 1) that may advantageously replace synthetic nanoparticles in some clinical contexts. Studies on VLPs are at an earlier stage of development but also demonstrated interesting properties in preclinical experiments. In the end, hybrid vectorization systems incorporating both synthetic and biological moieties may constitute a rational compromise between efficacy, biocompatibility and standardized manufacturing even if complex designs may generate additional difficulties for clinical development.


Half the cancer patients receive radiotherapy – which exploits the low resistance of tumor cells to radiation-induced DNA damages – during their course of treatment [172]. Overexposure of healthy cells to radiations leads to radiotherapy-related toxicities that could be partially addressed using appropriate vectorization strategies. For external-beam radiotherapy [173] – or for related photodynamic therapy (PDT) that uses non-ionizing wavelengths [163] – nanovectors can sensitize tumors to radiations. For internal radiotherapy, nanomedicine is an elegant solution to deliver specifically radioelements to tumors and an alternative to the use of radiolabeled antibodies in radioimmunotherapy approaches [174].

  1. a.


Radiations not only cause direct damages to biomolecules but also generate reactive oxygen species (ROS). This phenomenon can be enhanced in tumors by the vectorization of radiosensitizing molecules that increase either ROS production in response to ionizing beams or malignant cell sensitivity to both direct and indirect radiation effects [175]. Gold nanoparticles (AuNPs) are well-characterized for their radiosensitizing properties [176]; their concentration in tumors increases the dose delivered locally during radiotherapy, resulting in ROS production, DNA repair machinery impairment and improved treatment efficacy. However, the clinical translation of these metallic nanoparticles remains challenging because of both their tendency to aggregate after systemic injection and their long-term toxicity due to liver accumulation. An alternative are chemical ROS-generating photosensitizers that can be coupled to a wide variety of biocompatible nanoparticles for PDT [177, 178]. Interestingly, some chemical radiosensitizers are also able to self-assemble to generate nanostructures by themselves [179]. Upconverting nanoparticles were recently modified to assemble with a photosensitizer in vivo by click chemistry after systemic injection [180]. These nanoparticles are able to convert low energy near-infrared light into high energy photons that activate the photosensitizer to generate ROS and achieved inhibition of tumor growth in an ectopic breast cancer model. A recent study used EVs purified from mouse blood and surface-loaded with the photosensitizer protoporphyrin IX (PplX) in a two-stage irradiation protocol to efficiently deliver PplX and induce apoptosis by PDT in a breast tumor model [181]. The porphyrin photosensitizer has also been effectively vectorized with M13 filamentous phage VLPs retargeted to mammary cancer cells by a specific peptide displayed on the pVIII coat protein and demonstrated efficient cancer cell targeting and sensitization to PDT [182]. The lack of oxygen in the tumor hypoxic core can lead to radioresistance, which can be bypassed by developing nanoparticles with O2-elevating abilities or nano-radiosensitizers with diminished oxygen dependence [183]. As an example, mesoporous manganese dioxide nanoparticles are able to catalyze O2 production to actively reverse hypoxia in tumors. These nanoparticles were loaded with the photosensitizer acridin orange and exhibited enhanced radiotherapy efficacy both in vitro and in vivo in a lung cancer xenograft model [184]. Hypoxia-reverting liposomes [185], macromolecular nanoassemblies [186, 187] and other types of nanoparticles [177] have also been used for their photosensitizing properties.

The radiosensitizer family also encompasses all molecules able to enhance tumor cell sensitivity to radiation effects by interfering with essential cellular pathways like DNA repair, apoptosis induction or cell cycle progression. As such, chemotherapeutics are used as radiosensitizers at the clinical level [175] and their loading on chemically engineered nanoparticles have demonstrated radiosensitizing effects [185, 188, 189]. As for chemotherapy, SPIONs and gold nanoparticles alone or within a bigger organic nanoparticle can also mediate tumor radiosensitization through inhibition of DNA repair mechanisms by hyperthermia or photothermia, respectively [166]. DNA viruses are capable of impairing the DNA damage response [190] and some OVs (e.g. adenoviridae) naturally downregulate key proteins involved in the response to radiation-induced DNA damages [191], which makes them intrinsically radiosensitizing [192]. SiRNA-mediated gene silencing is another strategy to target genes involved in the cellular response to ionizing radiations [175]. As discussed below, OVs and VLPs are useful tools for such small RNA vectorization, an example being an adenovirus encoding a shRNA against the DNA-dependent protein kinase DNA damage response protein for local enhancement of radiotherapy in a human colorectal cancer xenograft model [193].

  1. b.

    Internal radiotherapy

Radionuclides have been vectorized for several years with various nanovectors like VLPs [194,195,196], EVs [197], nanoparticles [198, 199] or an oncolytic adenovirus [200] for cancer imaging, but for VLPs or EVs this has yet to be studied in therapeutic protocols. High-energy, short-range alpha-emitters have been conjugated to various types of chemically engineered nanoparticles with good therapeutic results but a large majority of radionuclides currently used in cancer therapy are low-energy beta-emitters with a longer path length [201]. Iodine 131 ( [143]I) is the most common nanoparticle-coupled radionuclide reported in the literature. Recent examples include PEGylated, nuclei-targeted [143]I-AuNPs tested in a colorectal cancer model [202] and [143]I-labeled, human serum albumin-bound manganese dioxide nanoparticles that were capable of significantly inhibiting tumor growth in a breast cancer model with a potentiating effect of MnO2 on radiotherapy efficacy [203]. In another study, treatment with PEGylated liposomes enclosing an [143]I-albumin core led to subcutaneous breast tumor shrinkage when co-administered either with liposomes containing a photosensitizer or with an anti-PD-L1 antibody [204]. In a very different strategy, OVs coding for the human sodium-iodine symporter (NIS) have been used to enhance the specific intake of [143]I in OV-infected tumor cells [99, 205,206,207]; OV-NIS are injected several days before [143]I and indirectly mediate the vectorization of the radioelement to tumors neo-expressing NIS.

As for chemotherapy, the different subfamilies of nanoparticles have been massively investigated to improve the efficacy of radiotherapy, but the low biocompatibility and biodegradability of inorganic nanoparticles called for the development of alternatives. Successful delivery of radiosensitizing molecules was achieved with organic nanoparticles and bio-inspired vectors such as EVs, while engineered VLPs can be chemically coupled to radionuclides. Viruses and other bio-derived vectors are also expected to define original approaches to exploit precise biological mechanisms that are involved for instance in the cellular response to radiations.

Delivery of nucleic acids

Malignant transformation results from gene alterations (e.g. deletions, amplifications, mutations, translocations, epigenetic or viral dysregulations) that displace the equilibrium between oncogene and tumor-suppressor gene expression. These alterations can be corrected or compensated using nucleic acids (DNA or RNA) for gene editing (over-expression or knock-out), direct induction of cell death by expression of toxic genes or by modulating gene expression. As free nucleic acids are rapidly degraded in the bloodstream and do not cross cell membranes, clinical translation of cancer gene therapy requires proper vectorization [208]. Viruses are particularly suited for this as they are naturally designed to deliver genes in targeted cells (Table 2). Transgenic viruses are also relatively simple to generate and they ensure a high level of transgene expression. Many studies were conducted with retrovirus-like particles (RLPs) [209], non-replicative adenoviruses [210] and AAVs [211], whereas other VLPs used for both their capacity to package DNA and their easy retargeting achieved lower transduction efficacy [68, 82, 212]. Despite several limitations – the main one being the cytoplasmic delivery of cargos initially addressed to the nucleus – nanoparticles (mainly lipid-based) have been extensively used for nucleic acid delivery [213,214,215]. Some strategies are developed to increase nanoparticle-mediated gene expression in tumor cells [216], for instance by using nuclear localization signals (NLS) or by vectorizing messenger RNAs [217].

Gene therapy

The most frequent genetic alterations in cancer being p53 mutations, most gene therapies consist in vectorizing a wild-type TP53. Restoring wild-type p53 functions triggers cell death specifically in highly-dividing tumor cells exhibiting genome instability. An example of a nanovector exploiting this mechanism is Gendicin, a p53-encoding adenoviral vector that was the first-in-class gene therapy treatment for head and neck cancer approved by the China Food and Drug Administration in 2003 [218]. While many years of clinical use demonstrated its safety, its efficacy remains limited. However, the co-vectorization of other tumor suppressors (e.g. ING4, PTEN) in the same vector demonstrated synergistic efficacy [83]. The enhanced vectorization potential and intrinsic tumor cytotoxicity of OVs were also exploited to transiently express tumor suppressors at high levels but still lack clinical assessment [129]. Regarding nanoparticles, liposomes containing p53-encoding plasmids are being evaluated against different types of solid cancers [219, 220], including in phase I/II clinical trials (NCT02354547, NCT02340156, NCT02340117).

Other studies focus on cancer gene editing to disable key oncogenes. An oncolytic myxoma virus carrying a CRISPR cassette targeting the NRAS oncogene demonstrated efficient gene editing in vivo along with prolonged survival in a xenograft model of rhabdomyosarcoma [221]. Similarly, a CRISPR-Cas12a-carrying oncolytic adenovirus efficiently edited EGFR in vivo specifically in xenografted lung adenocarcinoma cells [222]. Transgene-free retroviral VLPs loaded with Cas9-sgRNA ribonucleoproteins (“nanoblades”) that demonstrated in vivo genome editing capacity [223] and can be pseudotyped to modulate their cell tropism may also have interesting applications for cancer therapy. Alternatively, lipid-based nanoparticles [224] and macromolecular nanoassemblies [225, 226] have been successfully used to deliver CRISPR-Cas9-encoding plasmids for oncogene edition. As an example, tumor-targeted macromolecular nanoassemblies decorated with a NLS-containing peptide specifically delivered a CRISPR-Cas9 plasmid to the nuclei of lung cancer cells in vitro and efficiently knocked out the Catenin beta-1 gene [227]. Nevertheless, the dysregulation of tumor suppressor genes in cancer being frequently post-transcriptomic, this may limit the actual efficacy of gene editing. In addition, gene delivery mostly impacts the cells receiving the transgene and will have limited bystander effects. Other approaches may thus be more adapted to address the heterogeneity of malignant diseases.

Induction of cell death

Gene therapies for triggering specific tumor cell death include Gene-Directed Enzyme/Prodrug Therapy (GDEPT) [228] and cytotoxic gene therapy [229, 230]. GDEPT involves the tumor delivery of a transgene encoding an enzyme able to convert a non-toxic prodrug into a cytotoxic drug, the latter exerting its activity against the modified tumor cells and its surrounding environment. Such transgenes include the herpes simplex virus thymidine kinase (HSV-TK) gene, converting ganciclovir into ganciclovir-triphosphate and inhibiting DNA elongation [231], and the cytidine deaminase that converts 5-fluorocytosine into 5-fluorouracile [228]. VLPs (e.g. adenoviruses) are the most suitable and the more frequently used nanovectors for suicide gene therapy due to their high gene transfer potential [232, 233]. For OVs, HSV de facto expresses HSV-TK [234] but this transgene has also been vectorized by other viruses [235, 236]. Liposomes were also used to actively deliver a mRNA or a plasmid coding for the HSV-TK protein in a lung cancer mouse model [237]. The authors showed that both mRNA- and plasmid-carrying liposomes can mediate a significant inhibition of tumor growth following ganciclovir injection with a superiority of the mRNA formulation. In another example, HSV-TK plasmid-bearing macromolecular nanoassemblies demonstrated a significant therapeutic effect against invasive orthotopic human glioblastoma multiforme in mice [238].

Cytotoxic gene therapy on the other hand consists in delivering a cell death-triggering gene to tumors. To avoid off-target effects, the expression is generally controlled by a cancer- or tissue-specific promoter [229]. The main focus has been on tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-based cancer therapy, TNF-α and TRAIL being major mediators of death receptor-mediated apoptosis. Delivery of TNF-α- or TRAIL-encoding genes for secretion of the cognate proteins by tumor cells was reported with OVs [239], VLPs [82, 240] or nanoparticles [241] with evidence of a bystander effect. Interestingly, displaying the TRAIL protein on the surface of nanovectors has also demonstrated efficient TRAIL-mediated cell death induction of circulating tumor cells in different studies [242,243,244]. An alternative is the use of inducible suicide genes, an elegant example being the vectorization by adenoviral vectors [245] and AAVs [246] of the AP20187-dependent inducible version of caspase 9, activated after AP20187 treatment. Another example is the AAV vectorization of a CRISPR system targeting telomeres to induce tumor cell death [211]. Several pathogen-derived toxins have also been studied as cell death inducers for cancer cytotoxic gene therapy. An example is the tumor-specific, apoptosis-triggering viral protein apoptin that was encoded by lambda phage VLPs [247] or OVs [248] and induced significant tumor reduction in breast and lung cancer models, respectively. A recent innovative study described the design of macromolecular nanoassemblies loaded with a light-switchable transgene coding for the diphtheria toxin A inducible by blue laser light, a protocol that improved survival in a melanoma model [249]. In parallel to these gene delivery approaches, several groups also vectorized the different toxins as proteins to trigger selective cancer cell death with nanoparticles [250, 251], VLPs [131] and bacterial minicells [252].

Modulation of gene expression

Cellular pathways and gene expression can be precisely modulated by RNA interference (RNAi). This involves different types of small RNAs such as microRNAs (miRNAs) and small interfering RNAs (siRNAs) that interact with specific target mRNAs and stimulate their degradation or the inhibition of their translation [253]. The targeted inhibition of oncogenic mRNAs or miRNAs attracts attention but effective delivery of small RNAs for cancer treatment requires appropriate vectorization, in particular to reduce their degradation by nucleases. To date, siRNAs and miRNAs have been mostly vectorized by chemically engineered nanoparticles, in particular liposomes as extensively reviewed elsewhere [213, 254]. The safety of siRNA vectorization by liposomes – for instance against genes coding for the Ephrin type-A receptor 2 or B-cell lymphoma 2 (BCL-2) – is under evaluation in several ongoing clinical trials [125, 255]. SiRNAs directed against oncogenes (e.g. MYC, BRAF, BCL-2) have also been transported with macromolecular nanoassemblies or inorganic nanoparticles [256] and, more recently, an anti-survivin siRNA was efficiently vectorized with dendrimers that were further entrapped in tumor-derived EVs for treating mice bearing prostate carcinoma [54].

MiRNAs are naturally transported by EVs throughout the organism to modulate gene expression in neighboring or distant cells, both in physiological and pathological conditions [39]. This process was harnessed in several studies to deliver miRNAs or anti-miRNAs to cancer cells [47]. Human fibroblast-derived exosomes containing KrasG12D-targeted siRNAs were thus shown to mediate a better inhibition of tumor growth compared to liposomes in pancreatic cancer models [257]; this difference of efficacy was attributed to the lower immunogenicity and decreased clearance of exosomes. Similarly, mesenchymal stem cell-derived EVs were used to deliver several tumor-suppressing miRNAs to malignant cells by exploiting both their alleged natural tropism for tumors and immune evasion abilities [254, 258, 259]. Another example is the use of natural killer cell-derived exosomes loaded with a Let-7a miRNA-coupled dendrimer that were efficiently delivered in vivo to neuroblastoma cells [260]. However, the natural miRNA content of EVs may mediate unwanted effects in tumors and preclude clinical applications; one should carefully choose the EV donor cell type or opt for alternatives such as artificial exosome–mimetic nanoplatforms that simulate natural cell-derived exosomes but with a controlled composition [261]. Micro-organism-derived nanovectors are also a suitable alternative to vectorize miRNAs. In a phase I clinical trial, patients with malignant pleural mesothelioma were treated intravenously with EGFR-targeted bacterial minicells containing miRNA mimics [64]; the study concluded to treatment safety associated with a disease control rate of 65%, but the precise intake mechanism is still to be characterized. MS2 bacteriophage VLPs can be loaded with siRNAs or long non-coding RNAs and efficiently deliver their cargo in targeted cells [131, 262], whereas RLPs can be used for stable interfering RNA expression in cancer cells [263, 264]. Successful in vivo vectorization of siRNAs against the epigenetic regulator HDAC1 [265] or the viral oncogene E6 [266] was also achieved with OVs and was associated with prolonged survival in models of metastatic melanoma or cervical cancer, respectively.

To conclude, all nanovector families are investigated either in preclinical studies or clinical trials for the delivery of nucleic acids for cancer therapy (Table 3). On the one hand, gene therapy approaches are dominated by viral vectors (e.g. VLPs, OVs) (Table 2) due to their natural abilities to deliver to the nuclear compartment therapeutic transgenes that will be efficiently expressed. On the other hand, the efficient delivery of RNA molecules has been demonstrated for almost all types of nanovectors described in this review. EVs naturally transport small RNAs and present a high biocompatibility, but lipid-based nanoparticles, bacterial minicells and viruses are also adapted to such vectorization. With the expected boom of cancer gene therapies in the next few years, upcoming clinical studies will provide critical data to determine which vectors are the best compromise when considering efficient nucleic acid delivery, biocompatibility and ultimately clinical efficacy.

Tumor microenvironment modulation & immunotherapy

In recent years, cancer treatment has rapidly evolved from directly targeting malignant cells to treating the TME as a whole [267, 268]. The stromal and immune compartments that constitute this complex environment support cancer growth, maintenance, resistance and recurrence and can be targeted for destruction or reprogramming. New technologies like single-cell profiling continuously provide a better understanding of this tumor heterogeneity and help both deciphering the intertwined mechanisms involved and developing new rationale-based therapies to target them. This is perfectly illustrated by the breakthrough of cancer immunotherapies that use either immune activating signals (e.g. cytokines, agonist antibodies) or inhibitors of immunomodulating cues (e.g. immune checkpoint inhibitors). Nevertheless, limiting off-target toxicities and moderate efficacies call for improved vectorization to further refine these approaches. Nanovectors can modulate the pharmacokinetics of immunotherapies, deliver locally combination therapies and sometimes display an intrinsic therapeutic potential [269, 270] (Table 2).

  1. a.

    Removing life support

Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) secrete immunomodulatory cytokines, growth factors and pro-angiogenic molecules that participate in tumor maintenance [267, 268]. A valid strategy would consist in eliminating these stromal cells, for instance by using targeted nanoparticles to specifically deliver chemotherapies and/or photosensitizers to CAFs [271,272,273,274] or bisphosphonates and other cytotoxic molecules to TAMs [269, 275]. In these approaches, nanoparticles are actively targeted to CAFs and TAMs, mostly with FAP- or αSMA-specific molecules, or with mannose moieties, respectively. OVs have also been used for anti-CAF bispecific T cell engagers (BiTEs) delivery to selectively mediate CAF death via T cell activation [276, 277]. Interestingly, the use of OVs, which infect malignant cells and replicate in the TME, allows for continuous local production of anti-CAF BiTEs by infected tumor cells. OVs can also be addressed directly to CAFs by exploiting CAF-specific promoters [278] or receptors [279] as shown with an adenovirus and measles virus, respectively.

Endothelial cells are other important actors of the TME as they ensure nutrient and oxygen supply to growing tumors. To induce tumor cell death, the tumor vasculature can thus be impaired by vectorizing anti-angiogenics, mostly VEGF inhibitors or anti-VEGF siRNAs. Those have been developed as single agents over the last two decades but showed major side effects, such as hemorrhages or thromboses [280]. Anti-angiogenics have been vectorized efficiently with nanoparticles [280], bacterial minicells [61] and OVs [281], either by active targeting to the tumor endothelium (e.g. iRGD peptide) or by relying on the EPR effect. As an example, untargeted liposomes were used to co-deliver an anti-VEGF siRNA and etoposide and caused a significant inhibition of tumor growth in an orthotopic non-small cell lung cancer model compared to the combinations of either free drugs or the separate liposomal formulations [282]. Similarly, the anti-VEGF antibody bevacizumab and erlotinib were co-vectorized in pH-sensitive lipid-polymer hybrid nanoparticles and achieved significant inhibition of non-small cell lung cancer growth in mice [283].

  1. b.

    Reprogramming the environment

Normalizing the TME by modifying the phenotypes and functions of its cellular components has become a therapeutic strategy to beat cancer [284]. Since reprogramming myeloid cells toward anti-tumor phenotypes can promote favorable immune responses, several strategies aim at re-educating TAMs into pro-inflammatory M1-like macrophages [285]. This can be achieved using pro-inflammatory cytokines (e.g. IL-12), miRNAs or TLR agonists which systemic delivery was shown to be highly toxic unless vectorized by nanoparticles [285,286,287,288] or VLPs [289]. Other types of immunosuppressive cell types such as myeloid-derived suppressor cells or regulatory T cells can also be targeted by engineered nanoparticles [275] and OVs [290].

OVs display intrinsic properties (e.g. induction of immunogenic tumor cell death (ICD), release of damage- and pathogen-associated molecular patterns) that make them perfectly suited for such reprogramming approaches in cancer immunotherapy. Clinical trials reported that OV-induced ICD can be sufficient to induce an abscopal anti-cancer immune response and lead to tumor eradication [94, 291, 292]. OV infection also promotes T cell infiltration in the infected tumors and could improve the efficacy of immune checkpoint inhibitors [293]. The vectorization of immunomodulating transgenes with OVs or VLPs turns cancer cells into therapeutic factories within the TME [86, 294] as shown with immune checkpoint inhibitors encoded from engineered viruses [295, 296]. This changes the pharmacokinetics of immunotherapies and enables the use of potent immune activators (e.g. trimerized CD137L, IL-12) that are toxic or even lethal when used systematically without proper vectorization. It also facilitates combinations, for example by inserting into large DNA virus genomes multiple immunotherapeutic transgenes (e.g IL-12 + anti-PD-L1) targeting different immune mechanisms for synergistic effects with no additional toxicity [296,297,298].

To vectorize immunotherapies targeting the TME [126], nanoparticles are generally combined with ICD inducers (e.g. hyperthermia) on the same vector in order to stimulate immune cell recruitment and activation [269, 299,300,301]. Contrary to transgene vectorization by OVs, nanoparticles usually transport proteins, which does not allow spatial and temporal treatment amplification. Nevertheless, inhibitors of IL-10, TGF-β, indoleamine 2,3-dioxygenase immunosuppressive molecules [273], TLR agonists [302,303,304] or pro-inflammatory cytokines (e.g. IL-2, IL-15, TNF-α, IFN-γ) [15, 305,306,307,308] have been successfully addressed to the TME in preclinical models using different types of nanoparticles [275, 309]. Those have also been used to vectorize anti-OX40 [310] and anti-CD137 [311] agonist antibodies or anti-PD-1 [310] and anti-PD-L1 [312] antagonist antibodies in mice to enable efficient T cell activation in the TME [270, 299]. In an elegant study, a tritherapy consisting in an immune checkpoint inhibitor (i.e. anti-PD-L1) and two T cell activators (i.e. anti-CD3 and anti-CD28) conjugated on the same nanoparticle was shown to augment the therapeutic index of the combination against murine breast and colorectal cancers [313], which illustrates the versatility of nanoparticles in this context.

Recent clinical advances in cancer immunotherapy and TME reprogramming are yet to be enhanced efficiently by appropriate vectorization approaches. Viruses display natural abilities (e.g. transgene transport and expression, intrinsic immunogenicity) for this, with OVs also exhibiting replication and oncolysis properties that can further improve their therapeutic efficacy. The development of clinical-grade viruses may be however challenging and organic nanoparticles, which are investigated in numerous preclinical studies to deliver immunomodulating proteins to tumors, offer good alternatives when considering their multiple engineering possibilities. The most efficient designs are still to be identified in clinical studies but advances in vaccination strategies using nanoparticles, for instance regarding Covid-19, may accelerate these developments. As for VLPs, EVs and bacterial minicells, their ability to vectorize biomolecules to modulate the TME has been demonstrated but clinical evidence is still missing.


The last three decades have seen the discovery of a tremendous number of new anti-cancer molecules selected for their tumor-specific cytotoxicity and, more recently, for their ability to alter the TME. However, a large majority of the molecules identified on the bench fail in the clinic because of a poor efficacy/safety ratio after systemic administration. Despite personalized combinations to strike tumors on different fronts, resistance and toxicities are still major issues that limit many therapeutic applications. The advent of nanotechnologies opened an entirely novel area of research around the nanovectorization of anti-tumor therapeutics to both increase treatment efficacy and reduce associated toxicities by improving dramatically the specificity of tumor targeting. Chemically engineered nanoparticles – highly adaptable and for some relatively easy to manufacture – were the first to enter the clinic but with the current trend to improve the biocompatibility and to exploit precise biological mechanisms, bio-inspired nanovectors (e.g. VLPs, bacterial minicells, EVs, OVs) are now rapidly gaining interest. These different families of nanovectors allow the vectorization of almost all anti-cancer therapeutics, including chemical drugs, radio-elements, nucleic acids, toxins and immunotherapies (Table 2). To this day, chemotherapies, radioelements and molecules that sensitize tumors to radiotherapies have been more efficiently vectorized with synthetic nanoparticles but promising results have also been obtained with bacterial minicells and VLPs. By their very nature, viral vectors are the most suitable for gene therapy and nucleic acid vectorization, yet lipid-based nanoparticles have been extensively studied for these applications and may be more adapted – along with EVs or even bacterial minicells – to the delivery of small RNAs. Finally, nanoparticles can efficiently vectorize immunomodulatory proteins but OVs are becoming a new standard thanks to their intrinsic immunogenic properties and their ability to sustain local expression of immunomodulatory transgenes.

The field of nanovectorization is overly active and has already provided important advances for cancer therapy, with clinical approvals for several simple nanoformulations (Table 3). Current developments however focus on more complex structures including biological or bio-inspired objects. This opens opportunities for the advancement of personalized medicine by adapting rationally the nanovectors to specific biological contexts and clinical situations, but this also comes with several hurdles on the way to clinical applications. Indeed, the increasing complexity of synthetic nanoparticles, in particular for combination therapies, will necessitate radical optimization of production methods. For the bio-inspired nanovectors, the issues associated with the cost and the technical difficulties of large-scale productions still hinder their wider development. Moreover, the nanovectorization of anticancer therapeutics also lacks solid pharmacological and toxicological studies; improvements and solutions may come from advances in parallel fields such as recombinant protein production, conventional gene therapy or regenerative medicine. These problems highlight the importance of integrating the issue of therapeutic delivery in the process of drug development and call for a closer relationship with the field of drug discovery. As such, acknowledging the diversity of available delivery systems may act as a lever in drug discovery and reveal numerous therapeutic molecules that would have been rejected because of alleged unfavorable properties (e.g. poor solubility, high toxicity), thereby expanding the therapeutic arsenal against cancer.

Availability of data and materials

Not applicable.



adeno-associated virus


gold nanoparticle


cancer-associated fibroblast


extracellular matrix


epidermal growth factor receptor


enhanced permeability and retention


extracellular vesicle


gene-directed enzyme/prodrug therapy


multidrug resistance


sodium/iodide symporter


nitric oxide


oncolytic virus


polyacrylic acid


photodynamic therapy


polyethylene glycol


pH (low) insertion peptide


retrovirus-like particle


RNA interference


reactive oxygen species


super paramagnetic iron nanoparticle


tumor-associated macrophage


tumor microenvironment


virus-like particle


  1. 1.

    Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144:1941–53.

    CAS  Article  Google Scholar 

  2. 2.

    Björnmalm M, Thurecht KJ, Michael M, et al. Bridging Bio–Nano Science and Cancer Nanomedicine. ACS Nano. 2017;11:9594–613.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  3. 3.

    Shi J, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17:20–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Parodi A, Molinaro R, Sushnitha M, et al. Bio-inspired engineering of cell- and virus-like nanoparticles for drug delivery. Biomaterials. 2017;147:155–68.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021:1–18.

  6. 6.

    Liu J, Miao L, Sui J, et al. Nanoparticle cancer vaccines: Design considerations and recent advances. Asian J Pharm Sci. 2020;15:576–90.

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Sivasubramanian M, Chuang YC, Chen N-T, et al. Seeing Better and Going Deeper in Cancer Nanotheranostics. Int J Mol Sci. 2019;20:3490.

    CAS  PubMed Central  Article  Google Scholar 

  8. 8.

    Kumari P, Ghosh B, Biswas S. Nanocarriers for cancer-targeted drug delivery. J Drug Target. 2016;24:179–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Navya PN, Kaphle A, Srinivas SP, et al. Current trends and challenges in cancer management and therapy using designer nanomaterials. Nano Converg. 2019;6:23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Bayda S, Hadla M, Palazzolo S, et al. Inorganic Nanoparticles for Cancer Therapy: A Transition from Lab to Clinic. Curr Med Chem. 2018;25:4269–303.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Yang Y, Yu C. Advances in silica based nanoparticles for targeted cancer therapy. Nanomed. 2016;12:317–32.

    CAS  Article  Google Scholar 

  12. 12.

    Alyassin Y, Sayed EG, Mehta P, et al. Application of mesoporous silica nanoparticles as drug delivery carriers for chemotherapeutic agents. Drug Discov Today. 2020;25:1513–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Wicki A, Witzigmann D, Balasubramanian V, et al. Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications. J Controlled Release. 2015;200:138–57.

    CAS  Article  Google Scholar 

  14. 14.

    Jain A. Jain null. Advances in Tumor Targeted Liposomes. Curr Mol Med. 2018;18:44–57.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Tang W-L, Tang W-H, Li S-D. Cancer theranostic applications of lipid-based nanoparticles. Drug Discov Today. 2018;23:1159–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Bulbake U, Doppalapudi S, Kommineni N, et al. Liposomal Formulations in Clinical Use: An Updated Review. Pharmaceutics. 2017;9:12.

    PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    García-Pinel B, Porras-Alcalá C, Ortega-Rodríguez A, et al. Lipid-Based Nanoparticles: Application and Recent Advances in Cancer Treatment. Nanomaterials. 2019;9:638.

    PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Date T, Nimbalkar V, Kamat J, et al. Lipid-polymer hybrid nanocarriers for delivering cancer therapeutics. J Controlled Release. 2018;271:60–73.

    CAS  Article  Google Scholar 

  19. 19.

    Guo J, Huang L. Membrane-core nanoparticles for cancer nanomedicine. Adv Drug Deliv Rev. 2020;156:23–39.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Maeda H, Fang J, Inutsuka T, et al. Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol. 2003;3:319–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Nichols JW, Bae YHEPR. Evidence and fallacy. J Controlled Release. 2014;190:451–64.

    CAS  Article  Google Scholar 

  22. 22.

    Sindhwani S, Syed AM, Ngai J, et al. The entry of nanoparticles into solid tumours. Nat Mater. 2020;19:566–75.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Bahrami B, Hojjat-Farsangi M, Mohammadi H, et al. Nanoparticles and targeted drug delivery in cancer therapy. Immunol Lett. 2017;190:64–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Hu Y, Liu C, Muyldermans S. Nanobody-Based Delivery Systems for Diagnosis and Targeted Tumor Therapy. Front Immunol. 2017;8:1442.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Marques AC, Costa PJ, Velho S, et al. Functionalizing nanoparticles with cancer-targeting antibodies: A comparison of strategies. J Controlled Release. 2020;320:180–200.

    CAS  Article  Google Scholar 

  26. 26.

    Alshaer W, Hillaireau H, Fattal E. Aptamer-guided nanomedicines for anticancer drug delivery. Adv Drug Deliv Rev. 2018;134:122–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Zhong Y, Meng F, Deng C, et al. Ligand-directed active tumor-targeting polymeric nanoparticles for cancer chemotherapy. Biomacromolecules. 2014;15:1955–69.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Peng P, Yang K, Tong G, et al. Polysaccharide Nanoparticles for Targeted Cancer Therapies. Curr Drug Metab. 2018;19:781–92.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Hauser AK, Wydra RJ, Stocke NA, et al. Magnetic nanoparticles and nanocomposites for remote controlled therapies. J Controlled Release. 2015;219:76–94.

    CAS  Article  Google Scholar 

  30. 30.

    Sanchez-Cano C, Carril M. Recent Developments in the Design of Non-Biofouling Coatings for Nanoparticles and Surfaces. Int J Mol Sci. 2020;21:1007.

    CAS  PubMed Central  Article  Google Scholar 

  31. 31.

    Kozma GT, Shimizu T, Ishida T, et al. Anti-PEG antibodies: Properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Adv Drug Deliv Rev. 2020;154–155:163–75.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  32. 32.

    Jin Q, Deng Y, Chen X, et al. Rational Design of Cancer Nanomedicine for Simultaneous Stealth Surface and Enhanced Cellular Uptake. ACS Nano. 2019;13:954–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Bertrand N, Grenier P, Mahmoudi M, et al. Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics. Nat Commun. 2017;8:777.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Oh JY, Kim HS, Palanikumar L, et al. Cloaking nanoparticles with protein corona shield for targeted drug delivery. Nat Commun. 2018;9:4548.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Francia V, Yang K, Deville S, et al. Corona Composition Can Affect the Mechanisms Cells Use to Internalize Nanoparticles. ACS Nano. 2019;13:11107–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Liu D, Yang F, Xiong F, et al. The Smart Drug Delivery System and Its Clinical Potential. Theranostics. 2016;6:1306–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Abyaneh HS, Regenold M, McKee TD, et al. Towards extracellular matrix normalization for improved treatment of solid tumors. Theranostics. 2020;10:1960–80.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Pei D, Buyanova M. Overcoming Endosomal Entrapment in Drug Delivery. Bioconjug Chem. 2019;30:273–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020; 367: eaau6977.

  40. 40.

    Meng W, He C, Hao Y, et al. Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source. Drug Deliv. 2020;27:585–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Pullan JE, Confeld MI, Osborn JK, et al. Exosomes as Drug Carriers for Cancer Therapy. Mol Pharm. 2019;16:1789–98.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Rufino-Ramos D, Albuquerque PR, Carmona V, et al. Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases. J Controlled Release. 2017;262:247–58.

    CAS  Article  Google Scholar 

  43. 43.

    Liu C. Su C. Design strategies and application progress of therapeutic exosomes. Theranostics. 2019;9:1015–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Mathieu M, Martin-Jaular L, Lavieu G, et al. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Kooijmans SAA, Schiffelers RM, Zarovni N, et al. Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment. Pharmacol Res. 2016;111:487–500.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Qiao L, Hu S, Huang K, et al. Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs. Theranostics. 2020;10:3474–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Gilligan KE, Dwyer RM. Engineering Exosomes for Cancer Therapy. Int J Mol Sci. 2017;18:1122.

    PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Arrighetti N, Corbo C, Evangelopoulos M, et al. Exosome-like Nanovectors for Drug Delivery in Cancer. Curr Med Chem. 2019;26:6132–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Almeida JD, Edwards DC, Brand CM, et al. Formation of virosomes from influenza subunits and liposomes. Lancet. 1975;2:899–901.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Liu H, Tu Z, Feng F, et al. Virosome, a hybrid vehicle for efficient and safe drug delivery and its emerging application in cancer treatment. Acta Pharm. 2015;65:105–16.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Garofalo M, Villa A, Rizzi N, et al. Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice. J Controlled Release. 2019;294:165–75.

    CAS  Article  Google Scholar 

  52. 52.

    Lv P, Liu X, Chen X, et al. Genetically Engineered Cell Membrane Nanovesicles for Oncolytic Adenovirus Delivery: A Versatile Platform for Cancer Virotherapy. Nano Lett. 2019;19:2993–3001.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Zhang Y, Wu J, Zhang H, et al. Extracellular Vesicles-Mimetic Encapsulation Improves Oncolytic Viro-Immunotherapy in Tumors With Low Coxsackie and Adenovirus Receptor. Front Bioeng Biotechnol. 2020;8:e574007.

    Article  Google Scholar 

  54. 54.

    Zhupanyn P, Ewe A, Büch T, et al. Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes for enhanced siRNA delivery in vitro and in vivo. J Controlled Release. 2020;319:63–76.

    CAS  Article  Google Scholar 

  55. 55.

    MacDiarmid JA, Mugridge NB, Weiss JC, et al. Bacterially Derived 400 nm Particles for Encapsulation and Cancer Cell Targeting of Chemotherapeutics. Cancer Cell. 2007;11:431–45.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Khachatourians GG, Clark DJ, Adler HI, et al. Cell growth and division in Escherichia coli: a common genetic control involved in cell division and minicell formation. J Bacteriol. 1973;116:226–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    MacDiarmid JA, Minicells BH. Versatile vectors for targeted drug or si/shRNA cancer therapy. Curr Opin Biotechnol. 2011;22:909–16.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Taylor K, Howard CB, Jones ML, et al. Nanocell targeting using engineered bispecific antibodies. mAbs. 2015;7:53–65.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    MacDiarmid JA, Madrid-Weiss J, Amaro-Mugridge NB, et al. Bacterially-derived nanocells for tumor-targeted delivery of chemotherapeutics and cell cycle inhibitors. Cell Cycle. 2007;6:2099–105.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    MacDiarmid JA, Langova V, Bailey D, et al. Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model. PloS One. 2016;11:e0151832.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Jivrajani M, Nivsarkar M. Ligand-targeted bacterial minicells: Futuristic nano-sized drug delivery system for the efficient and cost effective delivery of shRNA to cancer cells. Nanomed. 2016;12:2485–98.

    CAS  Article  Google Scholar 

  62. 62.

    Solomon BJ, Desai J, Rosenthal M, et al. A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells. PLoS ONE. 2015;10:e0144559.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Whittle JR, Lickliter JD, Gan HK, et al. First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma. J Clin Neurosci. 2015;22:1889–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    van Zandwijk N, Pavlakis N, Kao SC, et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol. 2017;18:1386–96.

    PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Rohovie MJ, Nagasawa M, Swartz JR. Virus-like particles: Next-generation nanoparticles for targeted therapeutic delivery. Bioeng Transl Med. 2017;2:43–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Hulo C, de Castro E, Masson P, et al. ViralZone: a knowledge resource to understand virus diversity. Nucleic Acids Res. 2011;39:D576–82.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Wu W, Hsiao SC, Carrico ZM, et al. Genome-Free Viral Capsids as Multivalent Carriers for Taxol Delivery. Angew Chem Int Ed. 2009;48:9493–7.

    CAS  Article  Google Scholar 

  68. 68.

    Beatty PH, Lewis JD. Cowpea mosaic virus nanoparticles for cancer imaging and therapy. Adv Drug Deliv Rev. 2019;145:130–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Capsid Assembly CBHIV. Mechanism, and Structure. Biochemistry. 2016;55:2539–52.

    Article  CAS  Google Scholar 

  70. 70.

    Caldeira JC, Perrine M, Pericle F, et al. Virus-Like Particles as an Immunogenic Platform for Cancer Vaccines. Viruses. 2020;12:488.

    CAS  PubMed Central  Article  Google Scholar 

  71. 71.

    Hu H, Steinmetz NF. Cisplatin Prodrug-Loaded Nanoparticles Based on Physalis Mottle Virus for Cancer Therapy. Mol Pharm. 2020;17:4629–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Kaygisiz K, Synatschke CV. Materials promoting viral gene delivery. Biomater Sci. 2020;8:6113–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Czapar AE, Zheng Y-R, Riddell IA, et al. Tobacco Mosaic Virus Delivery of Phenanthriplatin for Cancer therapy. ACS Nano. 2016;10:4119–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Lee KW, Tan WS. Recombinant hepatitis B virus core particles: Association, dissociation and encapsidation of green fluorescent protein. J Virol Methods. 2008;151:172–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Tong GJ, Hsiao SC, Carrico ZM, et al. Viral Capsid DNA Aptamer Conjugates as Multivalent Cell-Targeting Vehicles. J Am Chem Soc. 2009;131:11174–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Geng Y, Dailhaimer P, Cai S, et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol. 2007;2:249–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Shukla S, Ablack AL, Wen AM, et al. Increased tumor homing and tissue penetration of the filamentous plant viral nanoparticle Potato virus X. Mol Pharm. 2013;10:33–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Suwan K, Yata T, Waramit S, et al. Next-generation of targeted AAVP vectors for systemic transgene delivery against cancer. Proc Natl Acad Sci U S A. 2019;116:18571–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Biabanikhankahdani R, Alitheen NBM, Ho KL, et al. pH-responsive Virus-like Nanoparticles with Enhanced Tumour-targeting Ligands for Cancer Drug Delivery. Sci Rep. 2016;6:37891.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. 2020;21:255–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    Masarapu H, Patel BK, Chariou PL, et al. Physalis Mottle Virus-Like Particles as Nanocarriers for Imaging Reagents and Drugs. Biomacromolecules. 2017;18:4141–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Smith TL, Yuan Z, Cardó-Vila M, et al. AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas. Proc Natl Acad Sci U S A. 2016;113:2466–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Zhang H, Zhou X, Xu C, et al. Synergistic tumor suppression by adenovirus-mediated ING4/PTEN double gene therapy for gastric cancer. Cancer Gene Ther. 2016;23:13–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Zhang J, Liu Y, Zang M, et al. Lentivirus-mediated CDglyTK gene-modified free flaps by intra-artery perfusion show targeted therapeutic efficacy in rat model of breast cancer. BMC Cancer. 2019;19:1–11.

    Article  Google Scholar 

  85. 85.

    Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18:498–513.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Aref S, Bailey K, Fielding A. Measles to the Rescue: A Review of Oncolytic Measles Virus. Viruses. 2016;8:294.

    PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Gromeier M, Nair SK. Recombinant Poliovirus for Cancer Immunotherapy. Annu Rev Med. 2018;69:289.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Delaunay T, Achard C, Boisgerault N, et al. Frequent Homozygous Deletions of Type I Interferon Genes in Pleural Mesothelioma Confer Sensitivity to Oncolytic Measles Virus. J Thorac Oncol. 2020;15:827–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Matveeva OV, Chumakov PM. Defects in interferon pathways as potential biomarkers of sensitivity to oncolytic viruses. Rev Med Virol. 2018;28:e2008.

    PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Takehara K, Tazawa H, Okada N, et al. Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer. Mol Cancer Ther. 2016;15:199–208.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Delaunay T, Violland M, Boisgerault N, et al. Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells. OncoImmunology. 2018;7:e1407897.

    PubMed  Article  PubMed Central  Google Scholar 

  93. 93.

    Alberts P, Tilgase A, Rasa A, et al. The advent of oncolytic virotherapy in oncology: The Rigvir® story. Eur J Pharmacol. 2018;837:117–26.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Andtbacka RHI, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33:2780–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Wei D, Xu J, Liu X-Y, et al. Fighting Cancer with Viruses: Oncolytic Virus Therapy in China. Hum Gene Ther. 2018;29:151–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    de Gruijl TD, Janssen AB, van Beusechem VW. Arming oncolytic viruses to leverage antitumor immunity. Expert Opin Biol Ther. 2015;15:959–71.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  97. 97.

    Andtbacka RHI, Collichio F, Harrington KJ, et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma. J Immunother Cancer. 2019;7:145.

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Naumenko V, Van S, Dastidar H, et al. Visualizing Oncolytic Virus-Host Interactions in Live Mice Using Intravital Microscopy. Mol Ther Oncolytics. 2018;10:14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Dispenzieri A, Tong C, LaPlant B, et al. Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma. Leukemia. 2017;31:2791–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    García M, Moreno R, Gil-Martin M, et al. A Phase 1 Trial of Oncolytic Adenovirus ICOVIR-5 Administered Intravenously to Cutaneous and Uveal Melanoma Patients. Hum Gene Ther. 2018;30:352–64.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  101. 101.

    Garcia-Carbonero R, Salazar R, Duran I, et al. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. J Immunother Cancer. 2017;5:71.

    PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Mell LK, Brumund KT, Daniels GA, et al. Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma. Clin Cancer Res. 2017;23:5696–702.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Russell SJ, Federspiel MJ, Peng K-W, et al. Remission of Disseminated Cancer After Systemic Oncolytic Virotherapy. Mayo Clin Proc. 2014;89:926–33.

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Ferguson MS, Lemoine NR, Wang Y. Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles. Adv Virol. 2012;2012:805629.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    Ricca JM, Oseledchyk A, Walther T, et al. Pre-existing Immunity to Oncolytic Virus Potentiates Its Immunotherapeutic Efficacy. Mol Ther. 2018;26:1008–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Xia M, Luo D, Dong J, et al. Graphene oxide arms oncolytic measles virus for improved effectiveness of cancer therapy. J Exp Clin Cancer Res. 2019;38:1–16.

    Article  Google Scholar 

  107. 107.

    Yokoda R, Nagalo B, Vernon B, et al. Oncolytic virus delivery: from nano-pharmacodynamics to enhanced oncolytic effect. Oncolytic Virotherapy. 2017;6:39–49.

    PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Ilett E, Kottke T, Thompson J, et al. Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy. Gene Ther. 2017;24:21–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Zhang Y-Q, Tsai Y-C, Monie A, et al. Enhancing the Therapeutic Effect Against Ovarian Cancer Through a Combination of Viral Oncolysis and Antigen-specific Immunotherapy. Mol Ther. 2010;18:692.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Ayala-Breton C, Barber GN, Russell SJ, et al. Retargeting Vesicular Stomatitis Virus Using Measles Virus Envelope Glycoproteins. Hum Gene Ther. 2012;23:484.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Muik A, Kneiske I, Werbizki M, et al. Notes: Pseudotyping Vesicular Stomatitis Virus with Lymphocytic Choriomeningitis Virus Glycoproteins Enhances Infectivity for Glioma Cells and Minimizes Neurotropism. J Virol. 2011;85:5679.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Qiao J, Moreno J, Sanchez-Perez L, et al. VSV-G pseudotyped, MuLV-based, semi-replication-competent retrovirus for cancer treatment. Gene Ther. 2006;13:1457–70.

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Bočkor L, Bortolussi G, Iaconcig A, et al. Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler–Najjar Syndrome Type I. Gene Ther. 2017;24:649–60.

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Hemminki O, Bauerschmitz G, Hemmi S, et al. Oncolytic adenovirus based on serotype 3. Cancer Gene Ther. 2011;18:288–96.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Stepanenko AA, Chekhonin VP. Tropism and transduction of oncolytic adenovirus 5 vectors in cancer therapy: Focus on fiber chimerism and mosaicism, hexon and pIX. Virus Res. 2018;257:40–51.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Magalhaes LG, Ferreira LLG, Recent Advances AAD. Perspectives in Cancer Drug Design. An Acad Bras Cienc. 2018;90:1233–50.

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Guo S, Vieweger M, Zhang K, et al. Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy. Nat Commun. 2020;11:972.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Wang N, Cheng X, Li N, et al. Nanocarriers and Their Loading Strategies. Adv Healthc Mater. 2019;8:1801002.

    Article  CAS  Google Scholar 

  119. 119.

    el Bahhaj F, Denis I, Pichavant L, et al. Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy. Theranostics. 2016;6:795–807.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. 120.

    Hong Y-D, Zhang J, Zhuang M, et al. Efficacy of decitabine-loaded gelatinases-stimuli nanoparticles in overcoming cancer drug resistance is mediated via its enhanced demethylating activity to transcription factor AP-2 epsilon. Oncotarget. 2017;8:114495–505.

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Naz A, Cui Y, Collins CJ, et al. PLGA-PEG nano-delivery system for epigenetic therapy. Biomed Pharmacother. 2017;90:586–97.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Roberti A, Valdes AF, Torrecillas R, et al. Epigenetics in cancer therapy and nanomedicine. Clin Epigenetics. 2019;11:1–18.

    Article  Google Scholar 

  123. 123.

    Li Z, Tan S, Li S, et al. Cancer drug delivery in the nano era: An overview and perspectives. Oncol Rep. 2017;38:611–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Anselmo AC, Mitragotri S. Nanoparticles in the clinic: An update. Bioeng Transl Med. 2019;4:e10143.

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Moss KH, Popova P, Hadrup SR, et al. Lipid Nanoparticles for Delivery of Therapeutic RNA Oligonucleotides. Mol Pharm. 2019;16:2265–77.

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Gupta J, Safdari HA, Hoque M. Nanoparticle mediated cancer immunotherapy. Semin Cancer Biol 2020;

  127. 127.

    Bobo D, Robinson KJ, Islam J, et al. Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date. Pharm Res. 2016;33:2373–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Kim SM, Yang Y, Oh SJ, et al. Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting. J Controlled Release. 2017;266:8–16.

    CAS  Article  Google Scholar 

  129. 129.

    Bressy C, Hastie E, Grdzelishvili VZ. Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy. Mol Ther Oncolytics. 2017;5:20–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Przystal JM, Waramit S, Pranjol MZI, et al. Efficacy of systemic temozolomide-activated phage-targeted gene therapy in human glioblastoma. EMBO Mol Med. 2019;e8492:11.

    Google Scholar 

  131. 131.

    Ashley CE, Carnes EC, Phillips GK, et al. Cell-Specific Delivery of Diverse Cargos by Bacteriophage MS2 Virus-Like Particles. ACS Nano. 2011;5:5729–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Freytag SO, Stricker H, Lu M, et al. Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys. 2014;89:268–76.

    PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Pei D-S, Di J-H, Chen F-F, et al. Oncolytic-adenovirus-expressed RNA interference for cancer therapy. Expert Opin Biol Ther. 2010;10:1331–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Anesti A-M, Simpson GR, Price T, et al. Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo. BMC Cancer. 2010;10:1–11.

    Article  CAS  Google Scholar 

  135. 135.

    Kiyokawa J, Kawamura Y, Ghouse SM, et al. Modification of Extracellular Matrix Enhances Oncolytic Adenovirus Immunotherapy in Glioblastoma. Clin Cancer Res 2020;

  136. 136.

    Yardley DA. nab-Paclitaxel mechanisms of action and delivery. J Controlled Release. 2013;170:365–72.

    CAS  Article  Google Scholar 

  137. 137.

    Schettini F, Giuliano M, De Placido S, et al. Nab-paclitaxel for the treatment of triple-negative breast cancer: Rationale, clinical data and future perspectives. Cancer Treat Rev. 2016;50:129–41.

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Biabanikhankahdani R, Bayat S, Ho KL, et al. A Simple Add-and-Display Method for Immobilisation of Cancer Drug on His-tagged Virus-like Nanoparticles for Controlled Drug Delivery. Sci Rep. 2017;7:5303.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139.

    Lam P, Lin R, Steinmetz NF. Delivery of mitoxantrone using a plant virus-based nanoparticle for the treatment of glioblastomas. J Mater Chem B. 2018;6:5888–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Le DHT, Lee KL, Shukla S, et al. Potato virus X, a filamentous plant viral nanoparticle for doxorubicin delivery in cancer therapy. Nanoscale. 2017;9:2348–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Lee KL, Murray AA, Le DHT, et al. Combination of Plant Virus Nanoparticle-Based in Situ Vaccination with Chemotherapy Potentiates Antitumor Response. Nano Lett. 2017;17:4019–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Lin RD, Steinmetz NF. Tobacco mosaic virus delivery of mitoxantrone for cancer therapy. Nanoscale. 2018;10:16307–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Yang Y, Chen Y, Zhang F, et al. Increased anti-tumour activity by exosomes derived from doxorubicin-treated tumour cells via heat stress. Int J Hyperthermia. 2015;31:498–506.

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Saari H, Lázaro-Ibáñez E, Viitala T, et al. Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. J Controlled Release. 2015;220:727–37.

    CAS  Article  Google Scholar 

  145. 145.

    Kim MS, Haney MJ, Zhao Y, et al. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations. Nanomed. 2018;14:195–204.

    CAS  Article  Google Scholar 

  146. 146.

    Naldi I, Taranta M, Gherardini L, et al. Novel epigenetic target therapy for prostate cancer: a preclinical study. PloS One. 2014;9:e98101.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. 147.

    Shafei A, El-Bakly W, Sobhy A, et al. A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer. Biomed Pharmacother. 2017;95:1209–18.

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Barenholz Y. (Chezy). Doxil® — The first FDA-approved nano-drug: Lessons learned. J Controlled Release. 2012;160:117–34.

    CAS  Article  Google Scholar 

  149. 149.

    Le DHT, Méndez-López E, Wang C, et al. Biodistribution of Filamentous Plant Virus Nanoparticles: Pepino Mosaic Virus versus Potato Virus X. Biomacromolecules. 2019;20:469–77.

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Rosenblum D, Joshi N, Tao W, et al. Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun. 2018;9:1410.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. 151.

    Jin Z, Lv Y, Cao H, et al. Core-shell nanocarriers with high paclitaxel loading for passive and active targeting. Sci Rep. 2016;6:27559.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Wang J. Combination Treatment of Cervical Cancer Using Folate-Decorated, pH-Sensitive, Carboplatin and Paclitaxel Co-Loaded Lipid-Polymer Hybrid Nanoparticles. Drug Des Devel Ther. 2020;14:823–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Wyatt LC, Moshnikova A, Crawford T, et al. Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors. Proc Natl Acad Sci U S A. 2018;115:E2811–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Zhang Y, Ji W, He L, et al. E. coli Nissle 1917-Derived Minicells for Targeted Delivery of Chemotherapeutic Drug to Hypoxic Regions for Cancer Therapy. Theranostics. 2018;8:1690–705.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Ganoth A, Merimi KC, Peer D. Overcoming multidrug resistance with nanomedicines. Expert Opin Drug Deliv. 2015;12:223–38.

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Dallavalle S, Dobričić V, Lazzarato L, et al. Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors. Drug Resist Updat. 2020;50:100682.

    PubMed  Article  Google Scholar 

  157. 157.

    Qi S-S, Sun J-H, Yu H-H, et al. Co-delivery nanoparticles of anti-cancer drugs for improving chemotherapy efficacy. Drug Deliv. 2017;24:1909–26.

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Bar-Zeev M, Livney YD, Assaraf YG. Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance. Drug Resist Updat. 2017;31:15–30.

    PubMed  Article  Google Scholar 

  159. 159.

    Meng H, Mai WX, Zhang H, et al. Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo. ACS Nano. 2013;7:994–1005.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    MacDiarmid JA, Amaro-Mugridge NB, Madrid-Weiss J, et al. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol. 2009;27:643–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  161. 161.

    Quintieri L, Geroni C, Fantin M, et al. Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res. 2005;11:1608–17.

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Sagnella SM, Yang L, Stubbs GE, et al. Cyto-Immuno-Therapy for Cancer: A Pathway Elicited by Tumor-Targeted, Cytotoxic Drug-Packaged Bacterially Derived Nanocells. Cancer Cell. 2020;37:354–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 163.

    Li X, Lovell JF, Yoon J, et al. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat Rev Clin Oncol. 2020;17:657–74.

    PubMed  Article  PubMed Central  Google Scholar 

  164. 164.

    Liu X, Zhang Y, Wang Y, et al. Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy. Theranostics. 2020;10:3793–815.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Liu Z, Shi J, Zhu B, et al. Development of a multifunctional gold nanoplatform for combined chemo-photothermal therapy against oral cancer. Nanomed. 2020;15:661–76.

    CAS  Article  Google Scholar 

  166. 166.

    Oei AL, Vriend LEM, Crezee J, et al. Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all. Radiat Oncol. 2015;10:1–13.

    CAS  Article  Google Scholar 

  167. 167.

    Paulides MM, Dobsicek Trefna H, Curto S, et al. Recent technological advancements in radiofrequency- andmicrowave-mediated hyperthermia for enhancing drug delivery. Adv Drug Deliv Rev. 2020;163–164:3–18.

    PubMed  Article  CAS  Google Scholar 

  168. 168.

    Ding Y, Du C, Qian J, et al. NIR-Responsive Polypeptide Nanocomposite Generates NO Gas, Mild Photothermia, and Chemotherapy to Reverse Multidrug-Resistant Cancer. Nano Lett. 2019;19:4362–70.

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Li M, Luo Z, Zhao Y. Hybrid Nanoparticles as Drug Carriers for Controlled Chemotherapy of Cancer. Chem Rec. 2016;16:1833–51.

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Gedda MR, Babele PK, Zahra K, et al. Epigenetic Aspects of Engineered Nanomaterials: Is the Collateral Damage Inevitable? Front Bioeng Biotechnol. 2019;7:228.

    PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Yu J, Loh XJ, Luo Y, et al. Insights into the epigenetic effects of nanomaterials on cells. Biomater Sci. 2020;8:763–75.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Citrin DE. Recent Developments in Radiotherapy. N Engl J Med. 2017;377:1065–75.

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Shirato H, Le Q-T, Kobashi K, et al. Selection of external beam radiotherapy approaches for precise and accurate cancer treatment. J Radiat Res (Tokyo). 2018;59:i2–i10.

    Article  Google Scholar 

  174. 174.

    Martins CD, Kramer-Marek G, Oyen WJG. Radioimmunotherapy for delivery of cytotoxic radioisotopes: current status and challenges. Expert Opin Drug Deliv. 2018;15:185–96.

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    Wang H, Mu X, He H, et al. Cancer Radiosensitizers. Trends Pharmacol Sci. 2018;39:24–48.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  176. 176.

    Her S, Jaffray DA, Allen C. Gold nanoparticles for applications in cancer radiotherapy: Mechanisms and recent advancements. Adv Drug Deliv Rev. 2017;109:84–101.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177.

    Chen J, Fan T, Xie Z, et al. Advances in nanomaterials for photodynamic therapy applications: Status and challenges. Biomaterials. 2020;237:119827.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  178. 178.

    Lan M, Zhao S, Liu W, et al. Photosensitizers for Photodynamic Therapy. Adv Healthc Mater. 2019;8:1900132.

    Article  CAS  Google Scholar 

  179. 179.

    Zheng Y, Li Z, Chen H, et al. Nanoparticle-based drug delivery systems for controllable photodynamic cancer therapy. Eur J Pharm Sci. 2020;144:105213.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  180. 180.

    Feng Y, Wu Y, Zuo J, et al. Assembly of upconversion nanophotosensitizer in vivo to achieve scatheless real-time imaging and selective photodynamic therapy. Biomaterials. 2019;201:33–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    Cheng H, Fan J-H, Zhao L-P, et al. Chimeric peptide engineered exosomes for dual-stage light guided plasma membrane and nucleus targeted photodynamic therapy. Biomaterials. 2019;211:14–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  182. 182.

    Gandra N, Abbineni G, Qu X, et al. Bacteriophage Bionanowire as a Carrier for Both Cancer-Targeting Peptides and Photosensitizers and its use in Selective Cancer Cell Killing by Photodynamic Therapy. Small. 2013;9:215–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  183. 183.

    Zhang C, Yan L, Gu Z, et al. Strategies based on metal-based nanoparticles for hypoxic-tumor radiotherapy. Chem Sci. 2019;10:6932–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Liu J, Zhang W, Kumar A, et al. Acridine Orange Encapsulated Mesoporous Manganese Dioxide Nanoparticles to Enhance Radiotherapy. Bioconjug Chem. 2020;31:82–92.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  185. 185.

    Jiang X, Zhang B, Zhou Z, et al. Enhancement of radiotherapy efficacy by pleiotropic liposomes encapsulated paclitaxel and perfluorotributylamine. Drug Deliv. 2017;24:1419–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  186. 186.

    Gao M, Liang C, Song X, et al. Erythrocyte-Membrane-Enveloped Perfluorocarbon as Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and Enhance Cancer Radiotherapy. Adv Mater. 2017;29:1701429.

    Article  CAS  Google Scholar 

  187. 187.

    Sheng Y, Nesbitt H, Callan B, et al. Oxygen generating nanoparticles for improved photodynamic therapy of hypoxic tumours. J Controlled Release. 2017;264:333–40.

    CAS  Article  Google Scholar 

  188. 188.

    Baldwin P, Van De Ven AL, Seitzer N, et al. Nanoformulation of the PARP Inhibitor Olaparib Enables Radiosensitization of a Radiation-Resistant Prostate Cancer Model. Int J Radiat Oncol. 2016;96:E595.

    Article  Google Scholar 

  189. 189.

    Liu H, Xie Y, Zhang Y, et al. Development of a hypoxia-triggered and hypoxic radiosensitized liposome as a doxorubicin carrier to promote synergetic chemo-/radio-therapy for glioma. Biomaterials. 2017;121:130–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  190. 190.

    Luftig MA. Viruses and the DNA Damage Response: Activation and Antagonism. Annu Rev Virol. 2014;1:605–25.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  191. 191.

    Martinez-Velez N, Marigil M, García-Moure M, et al. Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models. Acta Neuropathol Commun. 2019;7:64.

    PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    O’Cathail SM, Pokrovska TD, Maughan TS, et al. Combining Oncolytic Adenovirus with Radiation—A Paradigm for the Future of Radiosensitization. Front Oncol. 2017;7:153.

    PubMed  PubMed Central  Article  Google Scholar 

  193. 193.

    Kon T, Zhang X, Huang Q, et al. Oncolytic virus-mediated tumor radiosensitization in mice through DNA-PKcs-specific shRNA. Transl Cancer Res. 2012;1:4–14.

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    Dasa SSK, Jin Q, Chen C-T, et al. Target-Specific Copper Hybrid T7 Phage Particles. Langmuir. 2012;28:17372–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  195. 195.

    Farkas ME, Aanei IL, Behrens CR, et al. PET Imaging and biodistribution of chemically modified bacteriophage MS2. Mol Pharm. 2013;10:69–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  196. 196.

    Aanei IL, ElSohly AM, Farkas ME, et al. Biodistribution of Antibody-MS2 Viral Capsid Conjugates in Breast Cancer Models. Mol Pharm. 2016;13:3764–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  197. 197.

    Betzer O, Barnoy E, Sadan T, et al. Advances in imaging strategies for in vivo tracking of exosomes. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020;e1594:12.

    Google Scholar 

  198. 198.

    Lewis MR, Kannan R. Development and applications of radioactive nanoparticles for imaging of biological systems. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014;6:628–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  199. 199.

    Abou DS, Pickett JE, Thorek DLJ. Nuclear molecular imaging with nanoparticles: radiochemistry, applications and translation. Br J Radiol. 2015;88:20150185.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Mi Y-X, Li Y-C, Long Y-H. Imaging of radioiodine-labeled KH901, a tumor-specific oncolytic recombinant adenovirus, in nude mice with human hepatocellular carcinoma. Nucl Med Commun. 2010;31:405–10.

    PubMed  Article  PubMed Central  Google Scholar 

  201. 201.

    Jeon J. Review of Therapeutic Applications of Radiolabeled Functional Nanomaterials. Int J Mol Sci. 2019;20:2323.

    CAS  PubMed Central  Article  Google Scholar 

  202. 202.

    Su W, Chen C, Wang T, et al. Radionuclide-labeled gold nanoparticles for nuclei-targeting internal radio-immunity therapy. Mater Horiz. 2020;7:1115–25.

    CAS  Article  Google Scholar 

  203. 203.

    Tian L, Chen Q, Yi X, et al. Albumin-Templated Manganese Dioxide Nanoparticles for Enhanced Radioisotope Therapy. Small. 2017;13:1700640.

    Article  CAS  Google Scholar 

  204. 204.

    Liang C, Chao Y, Yi X, et al. Nanoparticle-mediated internal radioisotope therapy to locally increase the tumor vasculature permeability for synergistically improved cancer therapies. Biomaterials. 2019;197:368–79.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Gholami S, Chen C-H, Lou E, et al. Vaccinia virus GLV-1h153 in combination with 131I shows increased efficiency in treating triple-negative breast cancer. FASEB J. 2014;28:676–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Hakkarainen T, Rajecki M, Sarparanta M, et al. Targeted radiotherapy for prostate cancer with an oncolytic adenovirus coding for human sodium iodide symporter. Clin Cancer Res. 2009;15:5396–403.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  207. 207.

    Li H, Nakashima H, Decklever TD, et al. HSV-NIS, an oncolytic herpes simplex virus type 1 encoding human sodium iodide symporter for preclinical prostate cancer radiovirotherapy. Cancer Gene Ther. 2013;20:478–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. 208.

    McErlean EM, McCrudden CM, McCarthy HO. Delivery of nucleic acids for cancer gene therapy: overcoming extra- and intra-cellular barriers. Ther Deliv. 2016;7:619–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  209. 209.

    Park J-H, Seo J-H, Jeon H-Y, et al. Lentivirus-Mediated VEGF Knockdown Suppresses Gastric Cancer Cell Proliferation and Tumor Growth in vitro and in vivo. OncoTargets Ther. 2020;13:1331–41.

    CAS  Article  Google Scholar 

  210. 210.

    Bonetta AC, Mailly L, Robinet E, et al. Artificial microRNAs against the viral E6 protein provoke apoptosis in HPV positive cancer cells. Biochem Biophys Res Commun. 2015;465:658–64.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  211. 211.

    Dai W, Wu J, Wang D, et al. Cancer gene therapy by NF-κB-activated cancer cell-specific expression of CRISPR/Cas9 targeting telomeres. Gene Ther. 2020:1–15.

  212. 212.

    Zhu J, Tao P, Mahalingam M, et al. A prokaryotic-eukaryotic hybrid viral vector for delivery of large cargos of genes and proteins into human cells. Sci Adv. 2019;5:eaax0064.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    Wang H, Liu S, Jia L, et al. Nanostructured lipid carriers for MicroRNA delivery in tumor gene therapy. Cancer Cell Int. 2018;18:1–6.

    Article  CAS  Google Scholar 

  214. 214.

    Samaridou E, Heyes J, Lutwyche P. Lipid nanoparticles for nucleic acid delivery: Current perspectives. Adv Drug Deliv Rev. 2020;154–155:37–63.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  215. 215.

    Roma-Rodrigues C, Rivas-García L, Baptista PV, et al. Gene Therapy in Cancer Treatment: Why Go Nano? Pharmaceutics. 2020;12:233.

    CAS  PubMed Central  Article  Google Scholar 

  216. 216.

    Durymanov M, Reineke J. Non-viral Delivery of Nucleic Acids: Insight Into Mechanisms of Overcoming Intracellular Barriers. Front Pharmacol. 2018;9:971.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  217. 217.

    Gómez-Aguado I, Rodríguez-Castejón J, Vicente-Pascual M, et al. Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives. Nanomaterials. 2020;10:364.

    PubMed Central  Article  CAS  Google Scholar 

  218. 218.

    Zhang W-W, Li L, Li D, et al. The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic. Hum Gene Ther. 2018;29:160–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. 219.

    Chen X, Zhu Q, Xu X, et al. Sequentially Site-Specific Delivery of Apoptotic Protein and Tumor-Suppressor Gene for Combination Cancer Therapy. Small. 2019;15:e1902998.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  220. 220.

    Zuo L, Zhang F, Xu Y. Anti-EGF antibody cationic polymeric liposomes for delivery of the p53 gene for ovarian carcinoma therapy. Int J Clin Exp Pathol. 2019;12:205–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221.

    Phelps MP, Yang H, Patel S, et al. Oncolytic Virus-Mediated RAS Targeting in Rhabdomyosarcoma. Mol Ther Oncolytics. 2018;11:52–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  222. 222.

    Yoon A-R, Jung B-K, Choi E, et al. CRISPR-Cas12a with an oAd Induces Precise and Cancer-Specific Genomic Reprogramming of EGFR and Efficient Tumor Regression. Mol Ther. 2020;28:2286–96.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  223. 223.

    Mangeot PE, Risson V, Fusil F, et al. Genome editing in primary cells and in vivo using viral-derived Nanoblades loaded with Cas9-sgRNA ribonucleoproteins. Nat Commun. 2019;10:45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  224. 224.

    Zhen S, Li X. Liposomal delivery of CRISPR/Cas9. Cancer Gene Ther. 2019:1–13.

  225. 225.

    Liu C, Zhang L, Liu H, et al. Delivery Strategies of the CRISPR-Cas9 Gene-Editing System for Therapeutic Applications. J Controlled Release. 2017;266:17–26.

    CAS  Article  Google Scholar 

  226. 226.

    Tu K, Deng H, Kong L, et al. Reshaping Tumor Immune Microenvironment through Acidity-Responsive Nanoparticles Featured with CRISPR/Cas9-Mediated Programmed Death-Ligand 1 Attenuation and Chemotherapeutics-Induced Immunogenic Cell Death. ACS Appl Mater Interfaces. 2020;12:16018–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  227. 227.

    He X-Y, Ren X-H, Peng Y, et al. Aptamer/Peptide-Functionalized Genome-Editing System for Effective Immune Restoration through Reversal of PD-L1-Mediated Cancer Immunosuppression. Adv Mater. 2020;32:2000208.

    CAS  Article  Google Scholar 

  228. 228.

    Karjoo Z, Chen X, Progress HA. Problems with the Use of Suicide Genes for Targeted Cancer Therapy. Adv Drug Deliv Rev. 2016;99:113–28.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  229. 229.

    Glinka EM. Eukaryotic expression vectors bearing genes encoding cytotoxic proteins for cancer gene therapy. Plasmid. 2012;68:69–85.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  230. 230.

    Pahle J, Walther W. Bacterial Toxins for Oncoleaking Suicidal Cancer Gene Therapy. Recent Results Cancer Res. 2016;209:95–110.

    CAS  PubMed  Article  Google Scholar 

  231. 231.

    Düzgüneş N. Origins of Suicide Gene Therapy. Methods Mol Biol. 1895;2019:1–9.

    Google Scholar 

  232. 232.

    Kaplan JM. Adenovirus-Based Cancer Gene Therapy. Curr Gene Ther. 2005;5:595–605.

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Chen Z-H, Yu YP, Zuo Z-H, et al. Targeting genomic rearrangements in tumor cells through Cas9-mediated insertion of a suicide gene. Nat Biotechnol. 2017;35:543–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    Todo T, Rabkin SD, Martuza RL. Evaluation of ganciclovir-mediated enhancement of the antitumoral effect in oncolytic, multimutated herpes simplex virus type 1 (G207) therapy of brain tumors. Cancer Gene Ther. 2000;7:939–46.

    CAS  PubMed  Article  Google Scholar 

  235. 235.

    Islam SMBU, Lee B, Jiang F, et al. Engineering and Characterization of Oncolytic Vaccinia Virus Expressing Truncated Herpes Simplex Virus Thymidine Kinase. Cancers. 2020;12:228.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  236. 236.

    Zhang J-F, Wei F, Wang H-P, et al. Potent anti-tumor activity of telomerase-dependent and HSV-TK armed oncolytic adenovirus for non-small cell lung cancer in vitro and in vivo. J Exp Clin Cancer Res. 2010;29:1–7.

    Article  CAS  Google Scholar 

  237. 237.

    Wang Y, Su H-H, Yang Y, et al. Systemic delivery of modified mRNA encoding herpes simplex virus 1 thymidine kinase for targeted cancer gene therapy. Mol Ther. 2013;21:358–67.

    CAS  PubMed  Article  Google Scholar 

  238. 238.

    Gao S, Tian H, Xing Z, et al. A non-viral suicide gene delivery system traversing the blood brain barrier for non-invasive glioma targeting treatment. J Controlled Release. 2016;243:357–69.

    CAS  Article  Google Scholar 

  239. 239.

    Hu J, Wang H, Gu J, et al. Trail armed oncolytic poxvirus suppresses lung cancer cell by inducing apoptosis. Acta Biochim Biophys Sin. 2018;50:1018–27.

    CAS  PubMed  Article  Google Scholar 

  240. 240.

    Staquicini FI, Smith TL, Tang FHF, et al. Targeted AAVP-based therapy in a mouse model of human glioblastoma: a comparison of cytotoxic versus suicide gene delivery strategies. Cancer Gene Ther. 2020;27:301–10.

    CAS  PubMed  Article  Google Scholar 

  241. 241.

    Guimarães PPG, Gaglione S, Sewastianik T, et al. Nanoparticles for Immune Cytokine TRAIL-Based Cancer Therapy. ACS Nano. 2018;12:912–31.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  242. 242.

    Hu Q, Sun W, Qian C, et al. Anticancer Platelet-Mimicking Nanovehicles. Adv Mater. 2015;27:7043–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  243. 243.

    Wayne EC, Chandrasekaran S, Mitchell MJ, et al. TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer. J Controlled Release. 2016;223:215–23.

    CAS  Article  Google Scholar 

  244. 244.

    Li J, Ai Y, Wang L, et al. Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles. Biomaterials. 2016;76:52–65.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  245. 245.

    Xie X, Zhao X, Liu Y, et al. Adenovirus-mediated tissue-targeted expression of a caspase-9-based artificial death switch for the treatment of prostate cancer. Cancer Res. 2001;61:6795–804.

    CAS  PubMed  Google Scholar 

  246. 246.

    Khan N, Bammidi S, Chattopadhyay S, et al. Combination Suicide Gene Delivery with an Adeno-Associated Virus Vector Encoding Inducible Caspase-9 and a Chemical Inducer of Dimerization Is Effective in a Xenotransplantation Model of Hepatocellular Carcinoma. Bioconjug Chem. 2019;30:1754–62.

    CAS  PubMed  Article  Google Scholar 

  247. 247.

    Shoae-Hassani A, Keyhanvar P, Seifalian AM, et al. λ Phage Nanobioparticle Expressing Apoptin Efficiently Suppress Human Breast Carcinoma Tumor Growth In Vivo. PLoS ONE. 2013;8:e79907.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  248. 248.

    Yantao W, Wu Y, Zhang X, et al. Apoptin Enhances the Oncolytic Properties of Newcastle Disease Virus. Intervirology. 2012;55:276–86.

    Google Scholar 

  249. 249.

    He M, Wang Y, Chen X, et al. Spatiotemporally controllable diphtheria toxin expression using a light-switchable transgene system combining multifunctional nanoparticle delivery system for targeted melanoma therapy. J Controlled Release. 2020;319:1–14.

    CAS  Article  Google Scholar 

  250. 250.

    Asrorov AM, Gu Z, Min KA, et al. Advances on Tumor-Targeting Delivery of Cytotoxic Proteins. ACS Pharmacol Transl Sci. 2020;3:107–18.

    CAS  PubMed  Article  Google Scholar 

  251. 251.

    Gholami N, Cohan RA, Razavi A, et al. Cytotoxic and apoptotic properties of a novel nano-toxin formulation based on biologically synthesized silver nanoparticle loaded with recombinant truncated pseudomonas exotoxin A. J Cell Physiol. 2020;235:3711–20.

    CAS  PubMed  Article  Google Scholar 

  252. 252.

    Tsuji S, Chen X, Hancock B, et al. Preclinical evaluation of VAX-IP, a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer. Mol Ther Oncolytics. 2016;3:16004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  253. 253.

    Setten RL, Rossi JJ, Han S. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18:421–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  254. 254.

    O’Neill CP, Dwyer RM. Nanoparticle-Based Delivery of Tumor Suppressor microRNA for Cancer Therapy. Cells. 2020;9:521.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  255. 255.

    Kim HJ, Yi Y, Kim A, et al. Small Delivery Vehicles of siRNA for Enhanced Cancer Targeting. Biomacromolecules. 2018;19:2377–90.

    CAS  PubMed  Article  Google Scholar 

  256. 256.

    Zhang P, An K, Duan X, et al. Recent advances in siRNA delivery for cancer therapy using smart nanocarriers. Drug Discov Today. 2018;23:900–11.

    CAS  PubMed  Article  Google Scholar 

  257. 257.

    Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546:498–503.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  258. 258.

    O’Brien KP, Khan S, Gilligan KE, et al. Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379. Oncogene. 2018;37:2137–49.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  259. 259.

    Wang L, Yin P, Wang J, et al. Delivery of mesenchymal stem cells-derived extracellular vesicles with enriched miR-185 inhibits progression of OPMD. Artif Cells Nanomedicine Biotechnol. 2019;47:2481–91.

    CAS  Article  Google Scholar 

  260. 260.

    Wang G, Hu W, Chen H, et al. Cocktail Strategy Based on NK Cell-Derived Exosomes and Their Biomimetic Nanoparticles for Dual Tumor Therapy. Cancers. 2019;11:1560.

    CAS  PubMed Central  Article  Google Scholar 

  261. 261.

    Vázquez-Ríos AJ, Molina-Crespo Á, Bouzo BL, et al. Exosome-mimetic nanoplatforms for targeted cancer drug delivery. J Nanobiotechnology. 2019;17:1–15.

    Article  CAS  Google Scholar 

  262. 262.

    Chang L, Wang G, Jia T, et al. Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma. Oncotarget. 2016;7:23988–4004.

    PubMed  PubMed Central  Article  Google Scholar 

  263. 263.

    Wang T-Y, Zhang Q-Q, Zhang X, et al. The effect of recombinant lentiviral vector encoding miR-145 on human esophageal cancer cells. Tumour Biol. 2015;36:9733–8.

    CAS  PubMed  Article  Google Scholar 

  264. 264.

    Yu H, Zhu Z, Chang J, et al. Lentivirus-Mediated Silencing of Myosin VI Inhibits Proliferation and Cell Cycle Progression in Human Lung Cancer Cells. Chem Biol Drug Des. 2015;86:606–13.

    CAS  PubMed  Article  Google Scholar 

  265. 265.

    Schipper H, Alla V, Meier C, et al. Eradication of metastatic melanoma through cooperative expression of RNA-based HDAC1 inhibitor and p73 by oncolytic adenovirus. Oncotarget. 2014;5:5893–907.

    PubMed  PubMed Central  Article  Google Scholar 

  266. 266.

    Wang W, Sima N, Kong D, et al. Selective targeting of HPV-16 E6/E7 in cervical cancer cells with a potent oncolytic adenovirus and its enhanced effect with radiotherapy in vitro and vivo. Cancer Lett. 2010;291:67–75.

    CAS  PubMed  Article  Google Scholar 

  267. 267.

    Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol 2018; 15: 366–381.

  268. 268.

    Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  269. 269.

    Irvine DJ, Dane EL. Enhancing cancer immunotherapy with nanomedicine. Nat Rev Immunol. 2020;20:321–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  270. 270.

    Martin JD, Cabral H, Stylianopoulos T, et al. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol. 2020;17:251–66.

    PubMed  Article  Google Scholar 

  271. 271.

    Zhen Z, Tang W, Wang M, et al. Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy To Enhance Cytotoxic T Cell Infiltration and Tumor Control. Nano Lett. 2017;17:862–9.

    CAS  PubMed  Article  Google Scholar 

  272. 272.

    Zhu Y, Wen L, Shao S, et al. Inhibition of tumor-promoting stroma to enforce subsequently targeting AT1R on tumor cells by pathological inspired micelles. Biomaterials. 2018;161:33–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  273. 273.

    Truffi M, Mazzucchelli S, Bonizzi A, et al. Nano-Strategies to Target Breast Cancer-Associated Fibroblasts: Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy. Int J Mol Sci. 2019;20:1263.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  274. 274.

    Yu Q, Qiu Y, Li J, et al. Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy. J Controlled Release. 2020;321:564–75.

    CAS  Article  Google Scholar 

  275. 275.

    Gao S, Yang D, Fang Y, et al. Engineering Nanoparticles for Targeted Remodeling of the Tumor Microenvironment to Improve Cancer Immunotherapy. Theranostics. 2019;9:126–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  276. 276.

    Freedman JD, Duffy MR, Lei-Rossmann J, et al. An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells. Cancer Res. 2018;78:6852–65.

    CAS  PubMed  Article  Google Scholar 

  277. 277.

    de Sostoa J, Fajardo CA, Moreno R, et al. Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager. J Immunother Cancer. 2019;7:19.

    PubMed  PubMed Central  Article  Google Scholar 

  278. 278.

    Lopez MV, Rivera AA, Viale DL, et al. A Tumor-stroma Targeted Oncolytic Adenovirus Replicated in Human Ovary Cancer Samples and Inhibited Growth of Disseminated Solid Tumors in Mice. Mol Ther. 2012;20:2222–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  279. 279.

    Jing Y, Chavez V, Ban Y, et al. Molecular Effects of Stromal Selective Targeting by uPAR Retargeted Oncolytic Virus in Breast Cancer. Mol Cancer Res. 2017;15:1410–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  280. 280.

    Mukherjee A, Madamsetty VS, Paul MK, et al. Recent Advancements of Nanomedicine towards Antiangiogenic Therapy in Cancer. Int J Mol Sci. 2020;21:455.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  281. 281.

    Adelfinger M, Bessler S, Frentzen A, et al. Preclinical Testing Oncolytic Vaccinia Virus Strain GLV-5b451 Expressing an Anti-VEGF Single-Chain Antibody for Canine Cancer Therapy. Viruses. 2015;7:4075–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  282. 282.

    Li F, Wang Y, Chen W, et al. Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect via Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment. Theranostics. 2019;9:5886–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  283. 283.

    Pang J, Xing H, Sun Y, et al. Non-small cell lung cancer combination therapy: Hyaluronic acid modified, epidermal growth factor receptor targeted, pH sensitive lipid-polymer hybrid nanoparticles for the delivery of erlotinib plus bevacizumab. Biomed Pharmacother. 2020;109861:125.

    Google Scholar 

  284. 284.

    Roy A, Li S-D. Modifying the tumor microenvironment using nanoparticle therapeutics. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2016;8:891–908.

    PubMed  PubMed Central  Article  Google Scholar 

  285. 285.

    Hu G, Guo M, Xu J, et al. Nanoparticles Targeting Macrophages as Potential Clinical Therapeutic Agents Against Cancer and Inflammation. Front Immunol. 2019;10:1998.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  286. 286.

    Rodell CB, Arlauckas SP, Cuccarese MF, et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat Biomed Eng. 2018;2:578–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  287. 287.

    Parayath NN, Parikh A, Amiji MM. Repolarization of Tumor-Associated Macrophages in a Genetically Engineered Nonsmall Cell Lung Cancer Model by Intraperitoneal Administration of Hyaluronic Acid-Based Nanoparticles Encapsulating MicroRNA-125b. Nano Lett. 2018;18:3571–9.

    CAS  PubMed  Article  Google Scholar 

  288. 288.

    Wang T, Zhang J, Hou T, et al. Selective targeting of tumor cells and tumor associated macrophages separately by twin-like core–shell nanoparticles for enhanced tumor-localized chemoimmunotherapy. Nanoscale. 2019;11:13934–46.

    CAS  PubMed  Article  Google Scholar 

  289. 289.

    Yang X, Yu X, Wei Y. Lentiviral delivery of novel fusion protein IL12/FasTI for cancer immune/gene therapy. PLoS ONE. 2018;13:e0201100.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  290. 290.

    Hou W, Sampath P, Rojas JJ, et al. Oncolytic Virus-Mediated Targeting of PGE2 in the Tumor Alters the Immune Status and Sensitizes Established and Resistant Tumors to Immunotherapy. Cancer Cell. 2016;30:108–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  291. 291.

    Morris DG, Feng X, DiFrancesco LM, et al. REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors. Invest New Drugs. 2013;31:696–706.

    CAS  PubMed  Article  Google Scholar 

  292. 292.

    Puzanov I, Milhem MM, Minor D, et al. Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. J Clin Oncol. 2016;34:2619–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  293. 293.

    Ribas A, Dummer R, Puzanov I, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170:1109–19.

    CAS  PubMed  Article  Google Scholar 

  294. 294.

    Harrington K, Freeman DJ, Kelly B, et al. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov. 2019;18:689–706.

    CAS  PubMed  Article  Google Scholar 

  295. 295.

    Vijayakumar G, McCroskery S, Palese P. Engineering Newcastle Disease Virus as an Oncolytic Vector for Intratumoral Delivery of Immune Checkpoint Inhibitors and Immunocytokines. J Virol. 2020;94:e01677–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  296. 296.

    Yan R, Zhou X, Chen X, et al. Enhancement of Oncolytic Activity of oHSV Expressing IL-12 and Anti PD-1 Antibody by Concurrent Administration of Exosomes Carrying CTLA-4 miRNA. Immunother Open Access. 2019;5:1–10.

    Article  Google Scholar 

  297. 297.

    Porter CE, Rosewell Shaw A, Jung Y, et al. Oncolytic Adenovirus Armed with BiTE, Cytokine, and Checkpoint Inhibitor Enables CAR T Cells to Control the Growth of Heterogeneous Tumors. Mol Ther. 2020;28:1251–62.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  298. 298.

    Watanabe K, Luo Y, Da T, et al. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight. 2018;e99573:3.

    Google Scholar 

  299. 299.

    Zhuang J, Holay M, Park JH, et al. Nanoparticle Delivery of Immunostimulatory Agents for Cancer Immunotherapy. Theranostics. 2019;9:7826–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  300. 300.

    Li W, Peng A, Wu H, et al. Anti-Cancer Nanomedicines: A Revolution of Tumor Immunotherapy. Front Immunol. 2020;e601497:11.

    Google Scholar 

  301. 301.

    Alzeibak R, Mishchenko TA, Shilyagina NY, et al. Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future. J Immunother Cancer. 2021;e001926:9.

    Google Scholar 

  302. 302.

    Nuhn L, De Koker S, Van Lint S, et al. Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses. Adv Mater. 2018;e1803397:30.

    Google Scholar 

  303. 303.

    Zhang L, Wu S, Qin Y, et al. Targeted Codelivery of an Antigen and Dual Agonists by Hybrid Nanoparticles for Enhanced Cancer Immunotherapy. Nano Lett. 2019;19:4237–49.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  304. 304.

    Kim H, Griffith TS, Panyam J. Poly(d,l-lactide-co-glycolide) Nanoparticles as Delivery Platforms for TLR7/8 Agonist-Based Cancer Vaccine. J Pharmacol Exp Ther. 2019;370:715–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  305. 305.

    Curnis F, Fiocchi M, Sacchi A, et al. NGR-tagged nano-gold: A new CD13-selective carrier for cytokine delivery to tumors. Nano Res. 2016;9:1393–408.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  306. 306.

    Kienzle A, Kurch S, Schlöder J, et al. Dendritic Mesoporous Silica Nanoparticles for pH-Stimuli-Responsive Drug Delivery of TNF-Alpha. Adv Healthc Mater. 2017;1700012:6.

    Google Scholar 

  307. 307.

    Song Q, Yin Y, Shang L, et al. Tumor Microenvironment Responsive Nanogel for the Combinatorial Antitumor Effect of Chemotherapy and Immunotherapy. Nano Lett. 2017;17:6366–75.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  308. 308.

    Yin Y, Hu Q, Xu C, et al. Co-delivery of Doxorubicin and Interferon-γ by Thermosensitive Nanoparticles for Cancer Immunochemotherapy. Mol Pharm. 2018;15:4161–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  309. 309.

    Locy H, de Mey S, de Mey W, et al. Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend. Front Immunol. 2909;2018:9.

    Google Scholar 

  310. 310.

    Mi Y, Smith CC, Yang F, et al. A Dual Immunotherapy Nanoparticle Improves T-Cell Activation and Cancer Immunotherapy. Adv Mater. 2018;e1706098:30.

    Google Scholar 

  311. 311.

    Zhang Y, Li N, Suh H, et al. Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity. Nat Commun. 2018;9:6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  312. 312.

    Emami F, Banstola A, Vatanara A, et al. Doxorubicin and Anti-PD-L1 Antibody Conjugated Gold Nanoparticles for Colorectal Cancer Photochemotherapy. Mol Pharm. 2019;16:1184–99.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  313. 313.

    Chiang C-S, Lin Y-J, Lee R, et al. Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy. Nat Nanotechnol. 2018;13:746–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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We thank Pr Elena Ishow, Ugo Hirigoyen and Thomas Ogor for proofreading of the manuscript.

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This work was supported by grants from La Ligue Contre le Cancer Grand Ouest, la Région Pays de la Loire, l’Université de Nantes and l’Agence Nationale de la Recherche (ANR-20-CE18-0009-01).

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TB, TP & NB initiated the study. TB, TP, MF, NN & NB performed the scientific literature search and designed the review structure. TB, TP & NB wrote the manuscript. TB, TP & MF designed the tables and figures. CB & NB supervised, helped to revise and edit the manuscript. All authors read and approved the final manuscript.

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Correspondence to Nicolas Boisgerault.

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Briolay, T., Petithomme, T., Fouet, M. et al. Delivery of cancer therapies by synthetic and bio-inspired nanovectors. Mol Cancer 20, 55 (2021).

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  • Cancer therapy
  • Vectorization
  • Nanomedicine
  • Drug delivery
  • Targeting
  • Virus
  • Nanoparticle
  • Vesicle